key: cord-0898093-663d0xv1
authors: Yong, Xin; Mao, Lejiao; Seaman, Matthew N.J.; Jia, Da
title: An Evolving Understanding of Sorting Signals for Endosomal Retrieve
date: 2022-04-13
journal: iScience
DOI: 10.1016/j.isci.2022.104254
sha: 67343908b5a2ab057e5ecc8b536d46ad859f9de8
doc_id: 898093
cord_uid: 663d0xv1

Complex mechanisms govern the sorting of membrane (cargo) proteins at endosomes to ensure that protein localization to the post-Golgi endomembrane system is accurately maintained. Endosomal retrieval complexes mediate sorting by recognizing specific motifs and signals in the cytoplasmic domains of cargo proteins transiting through endosomes. In this review, the recent progress in understanding the molecular mechanisms of how the retromer complex, in conjunction with sorting nexin (SNX) proteins, operates in cargo recognition and sorting is discussed. New data revealing the importance of different SNX proteins and detailing how post-translational modifications can modulate cargo sorting to respond to changes in the environment is highlighted along with the key role that endosomal protein sorting plays in SARS-CoV-2 infection.

in contrast, in the SNX3-retromer structure, both SNX3 and Vps26 dock directly to 113 the membrane, with Vps26 playing a dominant role. These observations indicate that 114 SNX3-retromer is sufficient to induce membrane curvature and tubulation without 115 classical membrane curvature drivers, such as BAR-domain containing proteins, and 116 suggest that retromer operates in a highly versatile manner by incorporating different 117 types of membrane adaptors and cargoes. Currently however, it is not yet established 118 that SNX3 with the retromer trimer is sufficient for tubule formation in vivo. The 119 close association of Vps26p with the membrane in yeast retromer also will enable 120 Vps26p to play a key role in cargo selection. Mammalian Vps26 can also directly 121 interact with cargo consistent with the retromer trimer functioning to sort cargo at 122 endosomes (Cui et al., 2019 , Lucas et al., 2016 , Fjorback et al., 2012 . 125 Metazoan-specific SNX27 is another member of the SNX family that associates with 126 retromer (Steinberg et al., 2013) . Unlike the SNX-BAR-retromer, or SNX3-retromer, 127 SNX27-retromer selectively recycles numerous cargoes exclusively to the plasma 128 membrane and is not required for endosome-to-TGN retrieval (Steinberg et al., of SNX27 binds type-I PDZ binding motifs (PDZbms), with the consensus sequence 135 [S/T]xΦ, located at the C-terminus of many cargoes (Clairfeuille et al., 2016) .

Interaction with the Vps26 subunit of retromer enhances the binding with PDZbms 137 (Gallon et al., 2014) . As SNX27, like SNX3, does not have a BAR domain, it will be 138 very interesting to determine how SNX27-retromer assembles on the membrane. It is 139 possible that an arrangement similar to SNX3-retromer is adopted by 

Both SNX1 and SNX2 harbor more than one DLF motif, which could be used to 149 promote and stabilize the formation of vesicular/tubular structures. As SNX27 is 150 known to interact with retromer, it has been proposed that SNX-BARs, SNX27 and 151 retromer form a "supercomplex" to promote the endosome-to-plasma membrane 152 recycling of cargoes containing SBM, PDZbm, or both (Yong et al., 2020, Yong et al., 153 2021c) (Fig 2) . The notion of an endosomal retrieval supercomplex could explain 154 many contradictory observations in the field. For instance, GLUT1 contains a 155 PDZbm, but its trafficking is regulated by not only SNX27 and retromer, but by 156 J o u r n a l P r e -p r o o f A more recent study further identify that Mvp1 mediates another endosomal 224 recycling pathway, independent of retromer and Snx4 (Suzuki et al., 2021) . Mvp1 225 binds to endosomal membrane protein Vps55 via its "YXTXXFM" motif, and is 226 responsible for Vps55 delivery to the Golgi (Suzuki et al., 2021) . The sorting motif (Cullen and Steinberg, 2018, Weeratunga et al., 2020) . In addition to ubiquitination, phosphorylation could also modulate the interaction between cargoes and ERCs, e.g. (Mao et al., 2021) . This alters the conformation of the SNX27 cargo-binding pocket, 260 reducing its interaction with cargoes and thereby inhibiting endocytic recycling 261 (Mao et al., 2021) . These studies demonstrate that the endosomal sorting processes 

There are a great many cargo proteins that traffic through endosomes to their 300 destination, be it the cell surface, the TGN or a lysosome. The different ERCs that 301 operate at endosomes all contribute to ensuring the process occurs with efficiency 302 and high fidelity. It is worth noting however that, simple eukaryotes such as yeast 303 employ a more modest array of ERCs which reflects the fact that there are both 304 fewer cargoes and also fewer destinations as yeast do not recycle proteins directly 305 from endosomes to the cell surface but retrieve first to the TGN/Golgi.

The strides made in understanding how cargoes are recognized have led to a much 308 more profound knowledge of the mechanisms of endosomal protein sorting.

Although SNX17-Commander and SNX-BARs has been recently identified as direct cargo recognition modules, it remains to be determined whether there additional 311 complexes responsible for cargo recognition and retrieve. Another major challenge 312 in the field is to dissect the molecular determinants for distinct sorting itineraries.

For instance, as retromer-linked SNX-BARs mediate both endosome-to-TGN and 314 endosome-to-plasma membrane trafficking of cargo proteins, how is the destination 315 of a particular cargo determined? The association of SNX-BARs with SNX27 316 suggests a potential synergy between different ERCs. It will be a major challenge 

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Research in the authors' laboratory is supported by Natural Science Foundation of 

All authors analyzed literature data and wrote the manuscript.

The authors declare no conflict of interest.J o u r n a l P r e -p r o o f