key: cord-013342-vx3eor43
authors: Silwal, Prashanta; Paik, Seungwha; Jeon, Sang Min; Jo, Eun-Kyeong
title: Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics
date: 2020-08-27
journal: Cells
DOI: 10.3390/cells9091979
sha: 
doc_id: 13342
cord_uid: vx3eor43

Autophagy is an intracellular process that targets intracellular pathogens for lysosomal degradation. Autophagy is tightly controlled at transcriptional and post-translational levels. Nuclear receptors (NRs) are a family of transcriptional factors that regulate the expression of gene sets involved in, for example, metabolic and immune homeostasis. Several NRs show promise as host-directed anti-infectives through the modulation of autophagy activities by their natural ligands or small molecules (agonists/antagonists). Here, we review the roles and mechanisms of NRs (vitamin D receptors, estrogen receptors, estrogen-related receptors, and peroxisome proliferator-activated receptors) in linking immunity and autophagy during infection. We also discuss the potential of emerging NRs (REV-ERBs, retinoic acid receptors, retinoic acid-related orphan receptors, liver X receptors, farnesoid X receptors, and thyroid hormone receptors) as candidate antimicrobials. The identification of novel roles and mechanisms for NRs will enable the development of autophagy-adjunctive therapeutics for emerging and re-emerging infectious diseases.

The NR superfamily classes are divided into four classes based on structural and functional characteristics, i.e., steroid receptors (Class I), retinoid X receptor (RXR) heterodimers (Class II), homodimeric orphan receptors (Class III), and monomeric orphan receptors (Class IV) [15, 61] . The NR superfamily is classified as the endocrine, adopted orphan, and orphan subfamilies, depending on the existence of ligands [61] (Figure 1 ). The differences in NR classes include their biological function, binding to a ligand or DNA, and tissue specificity. All members of the NR superfamily have a variable N-terminal domain (NTD), a DNA binding domain (DBD), a ligand-binding domain (LBD), and a variable C-terminal domain. NR DBD contains different DNA-binding recognition sequences and two zinc finger motifs for binding to chromatin [61, 62] . NRs play a crucial role in the recruitment of co-activators within the nucleus, although there is marked variability among the binding of NTDs to co-activators [15] . Autophagy processes such as macroautophagy, LC3-associated phagocytosis (LAP), and xenophagy involve different autophagy-related genes (ATGs) or cargo receptors, such as p62, NDP52, and optineurin. The upper panel highlights the different sets of autophagy genes involved in vesicle nucleation, autophagosome formation, and the maturation of autolysosomes. The NR superfamily classes are divided into three or four subclasses according to their structural and functional characteristics and their ligands. NRs are implicated in the regulation of autophagy at transcriptional and post-translational levels. Understanding the mechanisms by which NRs regulate the expression and post-translational modification of ATGs will facilitate the development of novel host-directed antimicrobial agents.

A total of 48 intracellular proteins have been identified as NRs [63] ; among them, several members are critical in the regulation of host immune responses to infection. These NRs include the vitamin D receptor (VDR), also known as nuclear receptor subfamily 1, group I, member 1 (NR1I1) [64] [65] [66] ; estrogen-related receptor-α (ERRα; ESRRA; NR3B1) [20, 67] ; ERRγ (ESRRG; NR3B3) [68] ; liver X receptor-α (LXRα; LXRA; NR1H3) [69] ; peroxisome proliferator-activated receptor-α (PPARα; Autophagy processes such as macroautophagy, LC3-associated phagocytosis (LAP), and xenophagy involve different autophagy-related genes (ATGs) or cargo receptors, such as p62, NDP52, and optineurin. The upper panel highlights the different sets of autophagy genes involved in vesicle nucleation, autophagosome formation, and the maturation of autolysosomes. The NR superfamily classes are divided into three or four subclasses according to their structural and functional characteristics and their ligands. NRs are implicated in the regulation of autophagy at transcriptional and post-translational levels. Understanding the mechanisms by which NRs regulate the expression and post-translational modification of ATGs will facilitate the development of novel host-directed antimicrobial agents.

A total of 48 intracellular proteins have been identified as NRs [63] ; among them, several members are critical in the regulation of host immune responses to infection. These NRs include the vitamin D receptor (VDR), also known as nuclear receptor subfamily 1, group I, member 1 (NR1I1) [64] [65] [66] ; estrogen-related receptor-α (ERRα; ESRRA; NR3B1) [20, 67] ; ERRγ (ESRRG; NR3B3) [68] ; liver X receptor-α (LXRα; LXRA; NR1H3) [69] ; peroxisome proliferator-activated receptor-α (PPARα; PPARA; NR1C1) [70] [71] [72] ; PPARγ (PPARG; NR1C3) [73] [74] [75] ; the glucocorticoid receptor (GR; GCR; NR3C1) [76] ; estrogen receptor-α (ERα; ESR1; NR3A); ERβ (ESR2; NR3A2) [77, 78] ; the xenobiotic pregnane X receptor (PXR; NR1I2) [79] [80] [81] ; rev-Erb-α (REV-ERBα; NR1D1) [82, 83] ; farnesoid X receptors (FXRs; NR1H4) [75, 84] ; nuclear receptor 4A (NR4A) family members; nuclear receptor related 1 protein (NURR1; NR4A2); and neuron-derived orphan receptor 1 (NOR1; NR4A3) [85] . The NRs are endogenously activated by small lipophilic ligands, such as steroid hormones, retinoids, and phospholipids; however, some of the NRs have been classified as 'orphan' members as their ligands have not yet been identified [86] . The ligands can cross the plasma membrane, directly interact with NRs inside the cells, and modulate gene transcription through different mechanisms [87] .

In class I NRs or steroid receptors, ligand binding at the plasma membrane is followed by a signal transduction cascade including enzymatic phosphorylation, which results in the translocation of transcription factors into the nucleus [61, 88] . ER, a member of the class I NR superfamily, is anchored in the cytoplasm by a chaperone protein such as heat shock protein 90 (HSP90). After ligand binding, the receptor is freed from the chaperone, causing homodimerization and nuclear translocation. In the nucleus, the ligand-receptor complex associates with the transcriptional coactivator and activates the target gene [89] . Selective estrogen receptor modulators (SERM) such as tamoxifen and bazedoxifen have been suggested to have antimycobacterial activity [90, 91] .

The class II receptor family includes the thyroid hormone receptor (TR), VDR, retinoic acid receptor (RAR), and PPAR [61] . They are typically present in the nucleus and generally form heterodimers with RXR [92] . The heterodimers are bound to their response element, even in the absence of a ligand, where gene activation is repressed through interaction with a nuclear co-repressor (NCoR) and silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) corepressor complexes. Binding of the ligand causes displacement of the NCoR/SMRT co-repressor, allowing transcriptional activation to occur [89, 93] . For VDR, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), which is the active form of vitamin D3 (hereafter referred to as vitamin D), acts as a ligand and activates functional VDR, which then recognizes and binds to vitamin D response elements (VDREs) located in the promoter region of target genes to control the transcription of those genes [94] . VDR signaling activation during infection leads to innate immune signals for the production of antimicrobial peptides (AMPs), such as human cathelicidin AMP (CAMP) and β-defensin 2, which are important in coordinating vitamin D-induced antimicrobial responses [95] . PPARs include three different isotypes: PPARα, PPARβ/δ (PPARD; NR1C2), and PPARγ. Each isoform has a different distribution and ligands [96] . They are activated after the binding of endogenous ligands, such as fatty acids and their derivatives, or synthetic modulators, such as GW7647 and GW501516, to the ligand-binding domain. PPARs form heterodimers with RXR, which, after ligand binding, results in the transactivation or repression of target genes through PPAR responsive elements (PPREs) [96, 97] . LXRs are the NRs which bind oxidized cholesterol derivatives such as oxysterols and intermediates of the cholesterol biosynthesis pathway [98] . The modulation of gene expression by LXR involves direct activation, repression, and transrepression [99] , and exhibits anti-inflammatory properties, as well as antimicrobial effects [98] .

Class III and IV receptors include the dimeric and monomeric orphan receptors, respectively. ERRα, one of the orphan nuclear receptors, is not regulated by the presence of natural ligands, but is regulated by post-transcriptional modifications, such as phosphorylation, sumoylation, or acetylation of the N-terminal domain [23, 100] , and is essential for antimicrobial host defense [23] . Other members of orphan NR include retinoic acid-related orphan receptors (ROR), whereas FXR and REV-ERB have been classified as adopted orphan receptors [92] . In addition, NRs are important in the regulation of autophagy [17, 20, 27, 101] , not only at the level of the transcription of ATGs, but also at the post-transcriptional level, by regulating protein-protein interactions, post-translational modification, and epigenetic mechanisms [21] [22] [23] 76, 102] . The contributions of NR modulation to defense against pathogens are beginning to be deciphered. Here, we focus on the roles of VDR, ER, ERR, and PPAR in autophagic host defense against infection and discuss other NRs as links between autophagy and innate immunity during infection ( Figure 2) . A deeper understanding of NR signaling and its underlying mechanisms will facilitate the development of autophagy-based host-directed anti-infectives. Cells 2020, 9, 1979 5 of 28 and its underlying mechanisms will facilitate the development of autophagy-based host-directed anti-infectives. have been shown to play critical functions in the regulation of autophagy-mediated host defensive immune responses during infection. These NRs regulate and participate in the autophagic signaling pathways not only at the transcriptional level, but also at the post-transcriptional level. VDR is one of the best characterized NRs related to autophagic function against various infections. It is well-known that VDR signaling increases autophagy activation via the induction of cathelicidin, which is a small cationic antimicrobial peptide. In addition, VDRs functionally link adaptive and innate immune responses by regulating downstream pathways of autophagy. ER activates autophagy by increasing reactive oxygen species (ROS) generation and Akt/ mammalian target of rapamycin (mTOR) signaling. ERRs, which are one of the orphan family members of NR, also regulate a variety of cellular responses, including autophagy. The induction of PGC-1α upregulates the ERRα to promote mitophagy and an antimicrobial effect through sirtuin 1. PPARα activation leads to the expression of transcription factor EB (TFEB) and its nuclear translocation, resulting in the enhancement of lysosomal biogenesis. PPARβ/δ prevents harmful ER stress by increasing autophagy markers Beclin-1 and LC3 II.

VDR signaling ameliorates infection and inflammation [66, 67, 103, 104] . Studies on the role of vitamin D in innate immunity have revealed that autophagy enhances phagosomal maturation and lysosomal function, and ameliorates inflammation and antimicrobial protein generation [67, 105, 106] . A physiological level of the active form of vitamin D (1α,25-dihydroxycholecalciferol) or functional activation of VDR signaling promotes autophagy activation in human monocytes or monocytic cells by inducing the synthesis of cathelicidin-a cationic antimicrobial peptide-which promotes phagosomal maturation in the presence of intracellular Mtb [107] [108] [109] or Mycobacterium marinum Figure 2 . Schematic representation of the signaling pathways of nuclear receptors (NRs) in autophagy-mediated host defense. NRs, including the vitamin D receptor (VDR), estrogen receptor (ER), estrogen-related receptors (ERRs), and peroxisome proliferator-activated receptors (PPARs) have been shown to play critical functions in the regulation of autophagy-mediated host defensive immune responses during infection. These NRs regulate and participate in the autophagic signaling pathways not only at the transcriptional level, but also at the post-transcriptional level. VDR is one of the best characterized NRs related to autophagic function against various infections. It is well-known that VDR signaling increases autophagy activation via the induction of cathelicidin, which is a small cationic antimicrobial peptide. In addition, VDRs functionally link adaptive and innate immune responses by regulating downstream pathways of autophagy. ER activates autophagy by increasing reactive oxygen species (ROS) generation and Akt/ mammalian target of rapamycin (mTOR) signaling. ERRs, which are one of the orphan family members of NR, also regulate a variety of cellular responses, including autophagy. The induction of PGC-1α upregulates the ERRα to promote mitophagy and an antimicrobial effect through sirtuin 1. PPARα activation leads to the expression of transcription factor EB (TFEB) and its nuclear translocation, resulting in the enhancement of lysosomal biogenesis. PPARβ/δ prevents harmful ER stress by increasing autophagy markers Beclin-1 and LC3 II.

VDR signaling ameliorates infection and inflammation [66, 67, 103, 104] . Studies on the role of vitamin D in innate immunity have revealed that autophagy enhances phagosomal maturation and lysosomal function, and ameliorates inflammation and antimicrobial protein generation [67, 105, 106] . A physiological level of the active form of vitamin D (1α,25-dihydroxycholecalciferol) or functional activation of VDR signaling promotes autophagy activation in human monocytes or monocytic cells by inducing the synthesis of cathelicidin-a cationic antimicrobial peptide-which promotes phagosomal maturation in the presence of intracellular Mtb [107] [108] [109] or Mycobacterium marinum [110] . In addition, vitamin D treatment and TLR8-mediated VDR signaling activation enhanced autophagy in human macrophages in a manner dependent on the ATG5 and Beclin-1, thereby inhibiting human immunodeficiency virus (HIV)-1 replication or the co-infection of HIV and Mtb [111] [112] [113] . Vitamin D-mediated autophagy and cathelicidin expression are negatively regulated by prostaglandin (PG)E2-an arachidonic acid-derived lipid mediator-via E prostanoid (EP)2 and EP4 receptors [114] .

Vitamin D supplementation in mice significantly induced VDR, cathelin-related antimicrobial peptide (CRAMP), and LC3B expression, but decreased the collagenase matrix metalloproteinase-1 [115] . A structural equation modeling analysis suggested that vitamin D-mediated autophagy reduces necrosis [115] . Additionally, clinical trials of vitamin D as adjunctive therapy to standard anti-tuberculosis (TB) treatment showed a significant decline in intracellular Mtb growth and the levels of proinflammatory cytokines/chemokines [116, 117] , but no clear effect on long-term sputum-smear conversion [118] . These data suggest that the vitamin D-autophagy pathway is associated with clinical recovery from TB. Nevertheless, further studies are needed to determine the effects and risks of vitamin D adjunctive therapy, as discussed by others [95, 119, 120] . We limit the discussion in this review to clinical trials of vitamin D therapy in TB and other infectious diseases.

IFN-γ, which is an important cytokine in the adaptive Th1 immune response, alone [121] or in combination with the CD40 ligand [122] , enhanced VDR-mediated antimicrobial defense in human monocytes/macrophages in vitamin D-sufficient serum. Vitamin D treatment was required for the expression of IL-12 [123] , and the combination of IL-12 and IL-18 in human macrophages enhanced the cell-autonomous production of IFN-γ and the autophagy-cathelicidin pathway, which upregulated the antimicrobial response to Mtb [124] . Therefore, functional VDR signaling links the adaptive and innate immune responses by regulating autophagy, phagosome-lysosome fusion, and cytokine production in Mtb infection.

Vitamin D treatment reversed the influenza A virus-induced inhibition of autophagic flux by inducing the expression of syntaxin-17 and the V-type proton ATPase subunit (ATP6V0A2) [125] . In addition, probiotic lactic-acid bacteria isolated from kimchi activated VDR-autophagy responses and enhanced the expression of ATG16L1 and Beclin-1, resulting in an anti-inflammatory and anti-infective effect in the intestines [126] . Vitamin D treatment restored the lysosomal function impaired by Helicobacter pylori in gastric epithelial cells, by activating-protein disulfide isomerase family A member 3 (PDIA3) receptor and upregulating mucolipin-3 (MCOLN3)-mediated Ca 2+ release [106] .

In an animal study of Aspergillus fumigatus infection, vitamin D treatment led to autophagic homeostasis by reducing the number of autophagy-mediated lysosomes and regulatory T-cells, thus enhancing the antimicrobial response [127] . Moreover, vitamin D suppressed rotavirus infection by upregulating the autophagy gene Beclin-1 and promoting autophagic maturation and cathelicidin gene expression [128] . Although vitamin D-induced autophagy is critical for an effective immune response, further studies are needed to determine the ability of vitamin D to prevent and treat infectious diseases in humans. The studies on VDR-related autophagy during infection are summarized in Table 1 . 

Estrogen-a female sex steroid hormone-and its receptors (ERα and ERβ) reportedly modulate autophagy, which is implicated in various human diseases and the determination of cell fate [21, 129] . Indeed, ERs and the downstream genomic and non-genomic signaling cascades affect the outcomes of tumorigenesis and angiogenesis in breast cancer [21, 130] . In addition, ERα activation by estrogen enhances autophagy and tumor cell survival in papillary thyroid cancer by promoting reactive oxygen species (ROS) generation and the activation of extracellular signal-regulated kinases [131] .

Estrogen modulators influence antimicrobial responses by influencing autophagy. The selective ER modulator bazedoxifene suppresses the intracellular growth of Mtb by activating autophagy via ROS generation and Akt/ mammalian target of rapamycin (mTOR) signaling [90] . Tamoxifen (TAM) is a potent inhibitor of Shiga toxin trafficking and toxicity in a manner independent on ERs [132] . TAM also restricted Toxoplasma replication by inducing xenophagy or autophagy [133] . Long-term treatment with 17β-estradiol (E2) exerted a beneficial effect on endotoxemia-associated circulatory and multiple organ dysfunction in ovariectomized rats, which was mediated, at least in part, by autophagy activation [134] . Clarification of the mechanisms through which ERs modulate autophagy and/or host defense, as well as the crosstalk between autophagy and immunity in the context of ER signaling, is needed for the development of novel therapeutic modalities for infection and inflammation.

ERRs are orphan members of the NR family, and are involved in a variety of biological responses, including cellular metabolism and energy control [135] [136] [137] . ERRα is a critical regulator of autophagy at transcriptional and post-translational levels, particularly in cooperation with sirtuin 1. These effects promoted the antimicrobial response to Mtb [23] . The thyroid hormone upregulated the expression of ERRα by inducing PGC-1α (PPARGC1A), thus modulating mitochondrial biogenesis and mitophagy. Mechanistically, the thyroid hormone upregulated the autophagy-regulating kinase ULK1 through ERRα, which was required for the autophagic clearance of mitochondria, i.e., mitophagy [138] . In contrast, the inhibition of ERRα activity by the inverse agonist XCT790 induced autophagy and promoted the clearance of toxic protein aggregates, enhancing its neuroprotective effect [139] . There is a role for ERRα in host defense between intracellular bacteria and viruses [23, [140] [141] [142] . Therefore, future studies should clarify the role of ERRα in modulating autophagy and evaluate its therapeutic potential as an antimicrobial. The studies on ERs and ERRα-related autophagy during infection are summarized in Table 2 . PTC, papillary thyroid carcinoma; MCF-7, breast cancer cell line; ERK1/2, extracellular signal-regulated protein kinase; mTOR, mammalian target of rapamycin; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; BMDM, bone marrow-derived macrophages; SIRT1, sirtuin 1; PPARGC1A, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ULK1, unc-51 like autophagy activating kinase.

The nutrient-sensing NRs, PPARα and FXR, play reciprocal functions in the regulation of autophagy; PPARα enhances and FXR suppresses autophagy to enhance lipolysis [22] and ciliogenesis [143] . PPARα ameliorates inflammatory and injurious conditions by inducing autophagy in various cells and tissues [144, 145] . In addition, autophagy activation leads to PPARα activation by degrading nuclear receptor co-repressor 1 (NCoR1), which interacts with and suppresses the transactivation of PPARα [146] .

PPARα modulates antimicrobial responses to Mtb, Mycobacterium bovis bacillus Calmette-Guérin (BCG), or Mycobacterium abscessus by activating transcription factor EB (TFEB) [70] [71] [72] . In addition, PPARα deficiency resulted in an exaggerated inflammatory response to mycobacterial infection. Importantly, PPARα activation significantly reduced the lipid body number and size in macrophages infected with Mtb or M. bovis BCG, suggesting that PPARα contributes to lipid catabolism and reduces the foamy refuge during mycobacterial infection [72] . TFEB controlled the inflammatory response of host macrophages to Mtb or BCG infection [72] . However, TFEB was reportedly required for the induction of inflammatory cytokines and chemokines in macrophages infected with Staphylococcus aureus [147] .

Numerous agents have been reported to activate PPARα and enhance TFEB, thereby promoting lysosomal biogenesis in models of chronic inflammatory and degenerative diseases [148] [149] [150] [151] . Therefore, PPARα-activating drugs have potential for various infectious diseases. HIV infection inhibited autophagy in macrophages, promoting the intracellular survival of Mtb and non-tuberculous mycobacteria (NTM) [152] . Trehalose, which targets TFEB and PGC-1α [153] , activated the xenophagic flux to eradicate intracellular Mtb and NTM [152] . Mechanistically, Trehalose enhanced TFEB nuclear translocation and autophagy activation in an mucolipin 1 (MCOLN1)-dependent manner [152] . Because trehalose promotes the functionally active conformation of the N-terminal domain of the glucocorticoid receptor [154] , its antimicrobial effect may be mediated by GR signaling. Therefore, trehalose-induced autophagy may be involved in controlling co-morbidities of HIV and TB infections.

PPARβ/δ inhibits the ER stress induced by palmitate in AC16 cardiomyocytes by inducing expression of the autophagy markers Beclin-1 and LC3 II, thus preventing the harmful cardiac effects of ER stress [155] . The treatment of septic mice with the PPARβ/δ-agonist GW0742 improved long-term survival and protected against multiple organ injury and dysfunction by modulating inflammatory signaling and coagulation [156, 157] .

Amodiaquine, which is a selective anti-Plasmodium falciparum agent, suppresses autophagolysosomal degradation and PPARγ activity [158] . The PPARγ ligand HP24, which is a pyridinecarboxylic acid derivative, ameliorated the pathologic and inflammatory responses induced by Trypanosoma cruzi [159] . INT131, which is a novel non-thiazolidinedione and selective PPARγ modulator, has a beneficial anti-inflammatory effect on EcoHIV-infected glial cells and in a mouse model of EcoHIV infection [160] . However, whether PPARβ/δ or PPARγ activation exerts an antimicrobial effect by modulating autophagy is unclear. Further studies are needed to clarify the roles of PPARβ/δ and PPARγ in controlling the host response to infections in the context of autophagy activation. The studies on PPAR-related autophagy during infection are summarized in Table 3 . TFEB, transcription factor EB; eNOS, endothelial NOS; VEGF-A, vascular endothelial growth factor A; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.

The adopted orphan NR-REV-ERBα-is involved in adipogenesis, muscle differentiation, glucose/lipid metabolism, and the circadian rhythm [161] [162] [163] . REV-ERBα links the circadian rhythm and autophagy, and directly regulates the rhythmic expression of ATGs in zebrafish [164] . The key transcriptional regulators TFEB and TFE3 are required for the expression of REV-ERBα [162] , suggesting another link between autophagy and the circadian cycle.

During infection, REV-ERBα activation by GSK4112 exerted an anti-mycobacterial effect in macrophages by enhancing autophagy and lysosomal biogenesis and suppressing IL-10 synthesis [165] . However, the pharmacological activation of REV-ERBα and REV-ERBβ (NR1D2) using agonists inhibited autophagy and lipogenesis, thereby exerting an anticancer effect [163] . Moreover, the lysosomotropic REV-ERBβ ligand (ARN5187) inhibited autophagy and exerted a cytotoxic effect in breast cancer cells [166] . The over-expression of REV-ERBα in skeletal muscle induced mitochondrial activity and respiratory capacity, but repressed autophagy [167] . Therefore, REV-ERBα and REV-ERBβ may play diverse roles in autophagy regulation, depending on the cell type and pathological status. Because the circadian rhythm may be linked to the immune response to infection [168] [169] [170] , further studies should clarify the roles of REV-ERBα and REV-ERBβ in autophagy, the circadian rhythm, and the immune response to bacterial and fungal pathogens. All-trans retinoic acid and/or arsenic trioxide induced autophagy of the oncoprotein promyelocytic leukemia (PML)/RARA, suggesting RARα as a therapeutic target for acute PML [171, 172] . In addition, RARα activated autophagy in human primary B cells [173] and various types of cancer cells [174, 175] . The downregulation of RARα led to the upregulation of VDR expression in acute myeloid leukemia cells [176] . However, its role in autophagy during the antimicrobial response is unclear. RARα is reportedly a critical regulator of the maturation of monocyte-derived dendritic cells during HIV infection [177] , although its relevance to autophagy has not been evaluated.

Similarly, little is known about the role of RARβ in the regulation of autophagy during infection. RARβ has a tumor suppressive function and is involved in cell differentiation and apoptosis. Interestingly, the human papillomavirus type 16 (HPV16) E7 oncoprotein upregulated the mRNA and protein levels of RARβ in cervical cancer cells and in the cervix of K14E7 transgenic mice [178] . During human adenovirus infection, the RARβ mRNA and protein levels were downregulated, but the overexpression of RARβ decreased human adenovirus production [179] . Therefore, RARβ may have therapeutic effects for adenovirus infection, although the autophagy-mediated suppression of infection is unclear in RARβ-induced antiviral and anticancer effects. RORs are important in the regulation of the circadian clock, metabolic homeostasis, and tumorigenesis [180, 181] . Although RORs are emerging as therapeutic targets for tumors, their roles in the modulation of host defense during infection in the context of autophagy are unclear. Upon infection with highly pathogenic avian influenza viruses (HPAIV H5N1), RORα is synthesized and suppresses NF-κB signaling and the inflammatory response in monocytes, thereby contributing to the escape of H5N1 from the host inflammatory defenses [182] . RORα is a melatonin receptor and protects against ischemic heart injury and diabetic cardiomyopathy [183, 184] . The effect of melatonin on autophagy regulation has been reported in various normal and cancer cells [185, 186] . In addition, the protective effects of melatonin in various bacterial, viral, and parasitic infections have been characterized [187] [188] [189] [190] [191] . Melatonin treatment of Hodgkin lymphoma cells increased the expression of RORα, RORβ, and RORγ, and enhanced autophagy activation [192] . Therefore, it would be interesting to investigate the involvement of RORs in melatonin-mediated autophagy activation.

As a nutrient-sensing and autophagy-regulating NR, FXRα regulates hepatic autophagy to maintain the energy balance in the liver [22, 193] and inhibits autophagy-mediated ciliogenesis [143] . The inhibitory effect of FXRα is counteracted by PPARα, which activates autophagy [22, 143, 193] . Because PPARα is involved in the coordination of autophagy activation and antimicrobial defenses [72] , it would be interesting to investigate the role of FXRα.

In a model of cholestasis, the activation of autophagy maturation is inhibited in an FXR-dependent manner, partly as a result of the induction of Rubicon. However, ursodeoxycholic acid (UDCA), which is a non-FXR-agonistic bile acid, induced hepatic autophagy and reduced the expression of Rubicon, which is an inhibitor of autophagy [194] . In an autophagy-deficient liver, the expression of FXR and its downstream genes was inhibited, promoting cholestatic injury [195] . Therefore, the link between FXR and autophagy requires further investigation.

LXRα and LXRβ are negative regulators of cholesterol metabolism and inflammation [196, 197] . Both LXRs are important in the antimicrobial response to viral and bacterial infections [75] . Three synthetic LXR agonists (T0901317, GW3965, and LXR-623) had a long-lasting inhibitory effect on hepatitis B virus replication and gene expression [198] . In addition, both LXRα and LXRβ were required for the suppression of gammaherpesvirus reactivation by downregulating fatty acid and cholesterol synthesis in macrophages [199] , and for the inhibition of herpes simplex virus type 1 (HSV-1) by 25-hydroxycholesterol [200] . IL-36 and LXR signaling promoted anti-mycobacterial effects by inducing the expression of cholesterol-converting enzymes and regulating the expression of antimicrobial peptides [201] . In addition, LXR activation inhibited Salmonella infection by inducing the expression of the multifunctional enzyme CD38 [202] . LXRs are involved in the regulation of autophagy in various pathological conditions, including cancers [203, 204] . Therefore, further studies on the involvement of LXRs in modulating autophagy during infection with intracellular microbes are required. The thyroid hormone is a regulator of the metabolic rate, oxidative phosphorylation (OXPHOS), and ROS production [205, 206] , and a potent inducer of autophagy/mitophagy [207, 208] . Thyroid hormone suppresses the hepatic carcinogenesis induced by the HBV X protein by promoting mitochondrial turnover via autophagy activation. In addition, thyroid hormone/TR-induced hepatic PINK1 expression is associated with hepatic cellular carcinoma (HCC) progression and a poor prognosis [209] . One might expect that thyroid hormone is involved in the modulation of host antimicrobial responses through autophagy. However, it remains to be determined whether both TRα and TRβ contribute to pathogenesis or protective immunity to broader ranges of infections through autophagy modulation. The studies on several NRs with potential roles in connecting autophagy and host defense are summarized in Table 4 . Prevention of proper fusion of autophagolysosome with lysosomes by bile acids, through FXR-dependent induction of Rubicon [194] GW4064

In vivo mice with hepatic deletion of Atg7 or Atg5 with or without Nrf2 codeletion ↓ Liver injury NRF2 activation in autophagy deficiency leading to downregulation of FXR, causing cholestasis [195] LXR T0901317, GW3965, LXR-623 HBV/primary human hepatocytes, HepaRG cells -Anti-HBV effects Inhibition of cholesterol 7α-hydroxylase 1 (CYP7A1) mRNA levels [198] DDA Melanoma and AML cell lines, AML patients samples, in vivo mice ↑ Anti-tumor DDA acting as partial agonist on LRX to increase Nur77, Nor1, and LC3 expression [204] TR T3

HepG2, Huh7 cells ↑ Lipid metabolism Upregulation of C19orf80 expression, which is involved in lipid metabolism through breakdown of lipid droplets [208] Mice model of hepatocarcinogenesis, HepG2 cells ↑ Inhibition of hepatic DNA damage, inflammation, and carcinogenesis Induction of hepatic PINK1 expression, which ubiquitinates HBx protein to trigger mitophagy [209] CEBPB, CCAAT/enhancer-binding protein beta; TFEB, transcription factor EB; TFE3, transcription factor E3; LAMP1, lysosomal-associated membrane protein 1; IL, interleukin; LKB1, liver kinase B1; AMPK, AMP-activated protein kinase; DRAM2, DNA-damage regulated autophagy modulator; PML, promyelocytic leukemia; ATRA, all-trans-retinoic acid; HPAIV, highly pathogenic avian influenza virus; APL, acute promyelocytic leukemia; MI/R, myocardial ischemia/reperfusion; HL, Hodgkin lymphoma; RPE, retinal pigment epithelium cells; NRF2, nuclear factor erythroid 2-related factor 2; HBV, hepatitis B virus; DDA, dendrogenin A; Nur77, nerve growth factor IB; Nor1, neuron-derived orphan receptor 1; T3, triiodothyronine; PINK1, PTEN-induced kinase 1.

Given the role of autophagy in controlling intracellular pathogens, there is an urgent need for autophagy-directed therapeutics and prophylactics. The targeting of autophagy in monocytes/macrophages stimulates the innate immune response, the dampening of inflammation and suppression of innate immunity, and the promotion of pathogen escape [210] . Therefore, a more comprehensive understanding of the molecular mechanisms of crosstalk between autophagy and the innate immunity system in acute vs. chronic infection by various pathogens in immunocompetent vs. immunocompromised hosts will facilitate the development of therapeutics and vaccines.

NR protects against a variety of infections and modulates autophagy during pathogen invasion. Early studies exploited VDR-or ERRα-targeted antimicrobial responses and were followed by several trials expanding the effects of other NRs. It is known that the ATGs involved in non-canonical autophagy are different from those involved in canonical autophagy, but only a few studies on NR-mediated non-canonical autophagy pathways have been reported to date [211] . We are only beginning to answer important questions on the NR regulation of autophagy and innate immune responses. It is important to understand the signaling networks connecting NRs, autophagy, and the inflammatory and immune responses according to the infection stage and pathogen. Such an enhanced understanding will facilitate the development of novel antimicrobials. 

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How does estrogen work on autophagy?

Nutrient-sensing nuclear receptors coordinate autophagy

ESRRA (estrogen-related receptor alpha) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense

Migliorini Figueira, A.C. Modulation of nuclear receptor function: Targeting the protein-DNA interface

The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

New Insights in Glucocorticoid Receptor Signaling-More Than Just a Ligand-Binding Receptor

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

Autophagy in the pathogenesis of disease

Autophagy, immunity, and microbial adaptations

Autophagy in infection, inflammation and immunity

Autophagy and microbial pathogenesis

The role of Atg proteins in autophagosome formation

The ATG conjugation systems in autophagy

Biological Functions of Autophagy Genes: A Disease Perspective

Network organization of the human autophagy system

The Beclin 1 network regulates autophagy and apoptosis

Proikas-Cezanne, T. Canonical and non-canonical autophagy: Variations on a common theme of self-eating?

LC3-Associated Phagocytosis and Inflammation

The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression

Mechanism and medical implications of mammalian autophagy

Physiological Stress Response by Selective Autophagy

p62/SQSTM1-steering the cell through health and disease

Razani, B. p62/SQSTM1 and Selective Autophagy in Cardiometabolic Diseases

Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells

Autophagy signal transduction by ATG proteins: From hierarchies to networks

On the Fly: Recent Progress on

Autophagy and innate immunity: Insights from invertebrate model organisms

Regulation of autophagy: Modulation of the size and number of autophagosomes

How to control self-digestion: Transcriptional, post-transcriptional, and post-translational regulation of autophagy

The machinery of macroautophagy

The Three Musketeers of Autophagy: Phosphorylation, ubiquitylation and acetylation

The emerging role of acetylation in the regulation of autophagy

New targets for acetylation in autophagy

Posttranslational modification of autophagy-related proteins in macroautophagy

Roles of autophagy in elimination of intracellular bacterial pathogens

Autophagy subversion by bacteria

Autophagy and Mammalian Viruses: Roles in Immune Response, Viral Replication, and Beyond

Autophagy during viral infection-A double-edged sword

Viruses and autophagy

The nuclear receptor superfamily: The second decade

Determinants of target gene specificity for steroid/thyroid hormone receptors

Structural overview of the nuclear receptor superfamily: Insights into physiology and therapeutics

Vitamin D modulation of innate immune responses to respiratory viral infections

Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection

Autophagy: A new strategy for host-directed therapy of tuberculosis

Inverse agonist of estrogen-related receptor gamma controls Salmonella typhimurium infection by modulating host iron homeostasis

Liver X receptors contribute to the protective immune response against Mycobacterium tuberculosis in mice

The Peroxisome Proliferator-Activated Receptor alpha-Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections

SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions

PPAR-alpha Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

Peroxisome Proliferator-Activated Receptor-gamma agonists exhibit anti-inflammatory and antiviral effects in an EcoHIV mouse model

Mycobacterium tuberculosis and macrophage nuclear receptors: What we do and don't know

Macrophage nuclear receptors: Emerging key players in infectious diseases

The Interactome of the Glucocorticoid Receptor and Its Influence on the Actions of Glucocorticoids in Combatting Inflammatory and Infectious Diseases. Microbiol

Repurposing Estrogen Receptor Antagonists for the Treatment of Infectious Disease

Immunomodulatory Effects of 17beta-Estradiol on Epithelial Cells during Bacterial Infections

The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered by C difficile toxins

Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like

Human Xenobiotic Nuclear Receptor PXR Augments Mycobacterium tuberculosis Survival

Circadian clock proteins and immunity

The nuclear receptor REV-ERBalpha mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines

Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection

NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

The Nuclear Receptor Field: A Historical Overview and Future Challenges

Signals and Receptors

Flavonoids as dietary regulators of nuclear receptor activity

Signaling by nuclear receptors

Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy

Anti-Mycobacterial Activity of Tamoxifen Against Drug-Resistant and Intra-Macrophage Mycobacterium tuberculosis

The nuclear receptor superfamily: A structural perspective

Nuclear receptors: Coactivators, corepressors and chromatin remodeling in the control of transcription

The nuclear vitamin D receptor: Biological and molecular regulatory properties revealed

Vitamin D-Cathelicidin Axis: At the Crossroads between Protective Immunity and Pathological Inflammation during Infection

The role of Peroxisome Proliferator-Activated Receptors (PPAR) in immune responses

Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) acts as regulator of metabolism linked to multiple cellular functions

Integrating the roles of liver X receptors in inflammation and infection: Mechanisms and outcomes

The coregulator exchange in transcriptional functions of nuclear receptors

Phosphorylation-dependent sumoylation regulates estrogen-related receptor-alpha and -gamma transcriptional activity through a synergy control motif

Farnesoid X receptor: A "homeostat" for hepatic nutrient metabolism

Role of thyroid hormone in hepatic gene regulation, chromatin remodeling, and autophagy

Mycobacterial signaling through toll-like receptors

Vitamin D in Host Defense: Implications for Future Research

Vitamin D Axis in Inflammatory Bowel Diseases: Role, Current Uses and Future Perspectives

Vitamin D3 activates the autolysosomal degradation function against Helicobacter pylori through the PDIA3 receptor in gastric epithelial cells

Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin

Innate immunity to mycobacteria: Vitamin D and autophagy

Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling

Vitamin D-dependent cathelicidin inhibits Mycobacterium marinum infection in human monocytic cells

Hormonally active vitamin D3 (1alpha,25-dihydroxycholecalciferol) triggers autophagy in human macrophages that inhibits HIV-1 infection

Vitamin D inhibits human immunodeficiency virus type 1 and Mycobacterium tuberculosis infection in macrophages through the induction of autophagy

Toll-like receptor 8 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1

Prostaglandin E2 suppresses hCAP18/LL-37 expression in human macrophages via EP2/EP4: Implications for treatment of Mycobacterium tuberculosis infection

Vitamin D, cell death pathways, and tuberculosis

Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy

Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial

Daily adjunctive therapy with vitamin D3 and phenylbutyrate supports clinical recovery from pulmonary tuberculosis: A randomized controlled trial in Ethiopia

Vitamin D as Adjunctive Host-Directed Therapy in Tuberculosis: A Systematic Review

Impact of vitamin D on infectious disease

Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages

CD40 ligand and interferon-gamma induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes

The dynamic immunomodulatory effects of vitamin D3 during Mycobacterium infection

IL-12+IL-18 Cosignaling in Human Macrophages and Lung Epithelial Cells Activates Cathelicidin and Autophagy, Inhibiting Intracellular Mycobacterial Growth

Analysis of influenza virus-induced perturbation in autophagic flux and its modulation during Vitamin D3 mediated anti-apoptotic signaling

Lactic Acid Bacteria Isolated From Korean Kimchi Activate the Vitamin D Receptor-autophagy Signaling Pathways

Vitamin D enhances resistance to aspergillus fumigatus in mice via inhibition of excessive autophagy

Vitamin D3 supplementation alleviates rotavirus infection in pigs and IPEC-J2 cells via regulating the autophagy signaling pathway

Role of estrogen and its receptors mediated-autophagy in cell fate and human diseases

The complex nature of oestrogen signalling in breast cancer: Enemy or ally?

Estrogen receptor alpha induces prosurvival autophagy in papillary thyroid cancer via stimulating reactive oxygen species and extracellular signal regulated kinases

Tamoxifen blocks retrograde trafficking of Shiga toxin 1 and 2 and protects against lethal toxicosis

Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit Toxoplasma gondii Growth

Activation of autophagy is involved in the protective effect of 17beta-oestradiol on endotoxaemia-induced multiple organ dysfunction in ovariectomized rats

Transcriptional control of energy homeostasis by the estrogen-related receptors

Constitutive activities of estrogen-related receptors: Transcriptional regulation of metabolism by the ERR pathways in health and disease

The multiple universes of estrogen-related receptor alpha and gamma in metabolic control and related diseases

Thyroid hormone receptor and ERRalpha coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function

Modulation of Autophagy by a Small Molecule Inverse Agonist of ERRalpha Is Neuroprotective

Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense

Estrogen-related receptor alpha is required for efficient human cytomegalovirus replication

ERRalpha negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction

Ciliogenesis is reciprocally regulated by PPARA and NR1H4/FXR through controlling autophagy in vitro and in vivo

Peroxisome proliferator-activated receptor alpha activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway

Chondroprotection of PPARalpha activation by WY14643 via autophagy involving Akt and ERK in LPS-treated mouse chondrocytes and osteoarthritis model

Autophagy regulates lipid metabolism through selective turnover of NCoR1

Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes

PPARalpha Between Aspirin and Plaque Clearance

Cinnamic acid activates PPARalpha to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer's disease mouse model

Aspirin Induces Lysosomal Biogenesis and Attenuates Amyloid Plaque Pathology in a Mouse Model of Alzheimer's Disease via PPARalpha

Activation of peroxisome proliferator-activated receptor alpha induces lysosomal biogenesis in brain cells: Implications for lysosomal storage disorders

Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block

Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration

Trehalose induces functionally active conformation in the intrinsically disordered N-terminal domain of glucocorticoid receptor

PPARbeta/delta attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells

Delayed activation of PPAR-beta/delta improves long-term survival in mouse sepsis: Effects on organ inflammation and coagulation

Protective role of peroxisome proliferator-activated receptor-beta/delta in septic shock

Novel anti-adipogenic activity of anti-malarial amodiaquine through suppression of PPARgamma activity

Pyridinecarboxylic Acid Derivative Stimulates Pro-Angiogenic Mediators by PI3K/AKT/mTOR and Inhibits Reactive Nitrogen and Oxygen Species and NF-kappaB Activation Through a PPARgamma-Dependent Pathway in T. cruzi-Infected Macrophages

Selective peroxisome proliferator-activated receptor-gamma modulator, INT131 exhibits anti-inflammatory effects in an EcoHIV mouse model

Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta

Nutrient-sensitive transcription factors TFEB and TFE3 couple autophagy and metabolism to the peripheral clock

Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence

The circadian clock regulates autophagy directly through the nuclear hormone receptor Nr1d1/Rev-erbalpha and indirectly via Cebpb/(C/ebpbeta) in zebrafish

NR1D1 ameliorates Mycobacterium tuberculosis clearance through regulation of autophagy

Dual inhibition of REV-ERBbeta and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells

Rev-erb-alpha modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy

Circadian Coordination of Antimicrobial Responses

Immunity around the clock

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

MIR125B1 represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia

Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy

The lncRNA HOTAIRM1 regulates the degradation of PML-RARA oncoprotein and myeloid cell differentiation by enhancing the autophagy pathway

Activation of RARalpha induces autophagy in SKBR3 breast cancer cells and depletion of key autophagy genes enhances ATRA toxicity

Regulation of vitamin D receptor expression by retinoic acid receptor alpha in acute myeloid leukemia cells

A Comprehensive Map of the Monocyte-Derived Dendritic Cell Transcriptional Network Engaged upon Innate Sensing of HIV

Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice

Retinoic acid receptor beta, a potential therapeutic target in the inhibition of adenovirus replication

Retinoic Acid Receptor-Related Orphan Receptors: Critical Roles in Tumorigenesis

Retinoid-related orphan receptors (RORs): Critical roles in development, immunity, circadian rhythm, and cellular metabolism

Highly pathogenic influenza viruses inhibit inflammatory response in monocytes via activation of rar-related orphan receptor RORalpha

The nuclear melatonin receptor RORalpha is a novel endogenous defender against myocardial ischemia/reperfusion injury

Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-alpha in diabetic cardiomyopathy

Melatonin-mediated regulation of autophagy: Making sense of double-edged sword in cancer

Therapeutic potential of melatonin related to its role as an autophagy regulator: A review

T. cruzi infection among aged rats: Melatonin as a promising therapeutic molecule

The potential use of melatonin to treat protozoan parasitic infections: A review

Utilizing melatonin to combat bacterial infections and septic injury

Effects of melatonin on oxidative stress, and resistance to bacterial, parasitic, and viral infections: A review

Roles in influenza, Covid-19, and other viral infections

Melatonin triggers autophagic cell death by regulating RORC in Hodgkin lymphoma

Nutrient-sensing nuclear receptors PPARalpha and FXR control liver energy balance

FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis

Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury

Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells

Liver X receptors bridge hepatic lipid metabolism and inflammation

Activation of the liver X receptor pathway inhibits HBV replication in primary human hepatocytes

LXR Alpha Restricts Gammaherpesvirus Reactivation from Latently Infected Peritoneal Cells

Activation of liver X receptor plays a central role in antiviral actions of 25-hydroxycholesterol

Moura-Alves, P. IL-36/LXR axis modulates cholesterol metabolism and immune defense to Mycobacterium tuberculosis

The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism

Ligand-dependent transcriptional induction of lethal autophagy: A new perspective for cancer treatment

Dendrogenin A drives LXR to trigger lethal autophagy in cancers

Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling

Thyroid hormones and mitochondria: With a brief look at derivatives and analogues

Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy

Chromosome 19 open reading frame 80 is upregulated by thyroid hormone and modulates autophagy and lipid metabolism

Thyroid hormone protects hepatocytes from HBx-induced carcinogenesis by enhancing mitochondrial turnover

Targeting Autophagy in Innate Immune Cells: Angel or Demon during Infection and Vaccination? Front

Estrogen receptor alpha regulates non-canonical autophagy that provides stress resistance to neuroblastoma and breast cancer cells and involves BAG3 function

We are indebted to current and past members of our Medical Research Center (i-MRC) for discussions and investigations that contributed to this article. We apologize to colleagues whose work and publications could not be referenced owing to space constraints.

The authors declare no conflict of interest.