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Review
. 2020 Dec:179:229-236.
doi: 10.1016/j.biochi.2020.10.010. Epub 2020 Oct 25.

Membrane heist: Coronavirus host membrane remodeling during replication

Jingshu Zhang  1 , Yun Lan  2 , Sumana Sanyal  3
Affiliations
Review

Membrane heist: Coronavirus host membrane remodeling during replication

Jingshu Zhang et al. Biochimie. 2020 Dec.

Abstract

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 42 million people already, with more than one million deaths worldwide (as of October 25, 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.

Keywords: Coronavirus; Double membrane vesicles; Lipid metabolism.

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Conflict of interest statement

Declaration of competing interest The authors declare no commercial or financial conflicts of interest.

Figures

Fig. 1
Fig. 1
A brief comparation of typical DMVs generated by (+) RNA viruses. A) Coronavirus-induced DMVs are interconnected by their outer membrane via a narrow neck. These DMVs are part of an elaborate network that is connected with the rough ER. B) HCV-induced DMVs emerge as protrusions from the ER into the cytosol, connected to the ER membrane via a neck-like structure and in a close proximity to lipid droplets (LDs). This is different from the membrane invagination induced during replication of members of the Flavivirus genus [19]. C) Poliovirus-induced DMVs are generated from single-walled connecting and branching tubular compartments, which later transform into double-membrane structures by extending the membranous walls and/or collapsing of the lumenal cavity of the single-walled structures.
Fig. 2
Fig. 2
Biogenesis and architecture of coronavirus-induced DMVs with druggable targets and their pharmacological inhibitors. Formation of DMV is induced by viral nonstructural proteins (nsp3, nsp4, and nsp6) and host proteins involved in the ERAD machinery (EDEM1/OS9/SEL1). Two models have been proposed for the biogenesis of the coronavirus-induced DMVs: A) Model 1: viral infection triggers the generation of reticulovesicular network (RVN) of modified ER that integrates convoluted membranes (CMs) and numerous interconnected DMVs, which also connect to the ER. B) Model 2: by the action of nsp3, nsp4, and nsp6, formation of DMVs starts with exvaginations of the ER membrane, which then pinch off to form single-membraned EDEMsomes. These vesicles then undergo partial invagination to form cup-like structures that are then sealed to form DMVs. C) Heterotypical interaction between nsp3-nsp4 via their lumenal domains can induce membrane zipping and curvature which are essential for the formation of DMVs. D) nsp3 is one of the major constituents of the double-membrane spanning pore complex on coronavirus induced DMVs. VP: vesicle packets; SRE: sterol response elements; SREBP: sterol regulatory element-binding protein; vRNA: viral RNA.
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