key: cord-0924878-g3lfecp0 authors: Zhang, Jingshu; Lan, Yun; Sanyal, Sumana title: Membrane heist: Coronavirus host membrane remodeling during replication date: 2020-10-25 journal: Biochimie DOI: 10.1016/j.biochi.2020.10.010 sha: 5e250a57f2c5d2f75cdf5527d3c8dadebc7d8ae5 doc_id: 924878 cord_uid: g3lfecp0 The ongoing pandemic of COVID-19 (Coronavirus Disease-2019), a respiratory disease caused by the novel coronavirus strain, SARS-CoV-2, has affected more than 30 million people already, with more than 900 thousand deaths worldwide (as of September 28, 2020). We are in urgent need of therapeutic interventions that target the host-virus interface, which requires a molecular understanding of the SARS-CoV-2 life-cycle. Like other positive-sense RNA viruses, coronaviruses remodel intracellular membranes to form specialized viral replication compartments, including double-membrane vesicles (DMVs), where viral RNA genome replication takes place. Here we review the current knowledge of the structure, lipid composition, function, and biogenesis of coronavirus-induced DMVs, highlighting the druggable viral and cellular factors that are involved in the formation and function of DMVs. Prior to the emergence of Coronavirus Disease-2019 (COVID-19) caused by severe 2 acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the outbreak of highly approximately 50 to 250 nm of these DMVs as described in detail elsewhere 9, 10 . 52 The remodeled membranes in poliovirus-infected cells, however, show a distinctive 53 morphology with single-walled, connected and branched tubular compartments at 54 early stage of infection, which later transform into double-membrane structures with 55 a diameter of 100 -300 nm via extending the membranous walls and/or collapsing of 56 the lumenal cavity of the single-walled structures 11 ( Figure 1C) . 57 Two high pathogenicity coronaviruses, MERS-CoV and SARS-CoV, are well 58 documented to induce ER-derived DMVs 12, 13 . In SARS-CoV-infected Vero E6 cells, 59 DMVs that are distributed throughout the cytoplasm can be observed as early as 2h which remain connected to ER membranes via their outer membrane 12 ( Figure 1A) . 307 The hydrophobic domains of the nsp 3, 4, and 6 anchored to the ER membrane and 308 target the viral RTC to the unmodified ER. Particularly, heterotypical interaction 309 between nsp3-nsp4 via their lumenal domains can induce membrane zipping and 310 curvature that are essential for the formation of DMVs ( Figure 2C ). As the viral 311 replication proceeds, locally accumulated transmembrane Nsps may induce further 312 expansion, distortion, and rearrangement of ER membrane, while recruiting host 313 factors required for viral replication (Figure 2A) . 314 In this model, apart from the hydrophobic transmembrane domains, the occurrence 315 of non-membrane-spanning hydrophobic/amphipathic regions in nsp 3 and 6 may 316 also contribute to their membrane bending ability, and this feature seems to be 317 common among DMVs-inducing RNA viruses 58 . 318 EDEMosome-cargo receptors or directly LC3І as well as other ERAD effectors to the 348 site of replication by one or more of the transmembrane nsps (nsp3, 4, and/or 6). 349 The formation of DMVs starts with evaginations of the ER membrane, which then 350 pinch off to form single-membraned EDEMsomes. These vesicles then undergo 351 partial invagination to form a cup-like structure that is then sealed to form a DMV 63, 352 65 ( Figure 2B ). Although the direct interactions between coronavirus nsps and 353 EDEMsome components have not yet been identified, EDEM1, OS9 and LC3І were 354 detected to co-localize with nsp2/3. Moreover, EDEM1 is involved in the ER N-355 glycosylation processing 66 . It is possible that the interaction between EDEM1 and 356 glycoprotein nsp6 is essential for the formation of DMVs 65 . 357 A very recent SARS-CoV-2 drug screening project using affinity-purification mass 377 spectrometry successfully identified more than three hundred cellular factors that 378 interact with viral proteins, among which there are 66 druggable human factors 379 targeted by 69 compounds. Amongst the identified hits, the authors found an 380 interaction between SARS-CoV-2 nsp6 and human sigmaR1 6 . SigmaR1 is a unique 381 multifunctional ER membrane protein that is involved in lipid transport, ER stress, 382 and autophagy 69 . 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These DMVs are part of an elaborate network that is connected with 603 the rough ER. B) HCV-induced DMVs emerge as protrusions from the ER into the 604 cytosol, connected to the ER membrane via a neck-like structure and in a close 605 proximity to lipid droplet (LD). This is different from the membrane invagination 606induced during replication of members of the Flavivirus genus. C) Poliovirus-induced 607DMVs generated from single-walled connecting and branching tubular compartments, 608which later transform into double-membrane structures by extending the 609 membranous walls and/or collapsing of the lumenal cavity of the single-walled 610structures.