Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the COVID-19 (coronavirus disease 2019) pandemic, is a positive strand RNA (+RNA) virus. Like other +RNA viruses, SARS-CoV-2 is dependent on host cell metabolic machinery to survive and replicate, remodeling cellular membranes to generate sites of viral replication. Viral RNA-containing double-membrane vesicles (DMVs) are a striking feature of +RNA viral replication and are abundant in SARS-CoV-2–infected cells. Their generation involves rewiring of host lipid metabolism, including lipid biosynthetic pathways. Viruses can also redirect lipids from host cell organelles; lipid exchange at membrane contact sites, where the membranes of adjacent organelles are in close apposition, has been implicated in the replication of several +RNA viruses. Here we review current understanding of DMV biogenesis. With a focus on the exploitation of contact site machinery by +RNA viruses to generate replication organelles, we discuss evidence that similar mechanisms support SARS-CoV-2 replication, protecting its RNA from the host cell immune response.
Highlights
On entry into the host cell, the viral genome is released, and replication–transcription complexes (RTCs) are assembled that drive viral genome replication and expression of viral proteins
Hard to envisage a role for STARD3 as an LTP that enriches doublemembrane vesicles (DMVs) with endosomal sterol, and a recent study screening a CRISPR library for proteins required for SARS-CoV-2 infection found that neither endosomal STARD3 nor one of its endoplasmic reticulum (ER)-localized binding partners, MOSPD2 (Di Mattia et al, 2018), mediates viral infection or virus-induced cell death (Schneider et al, 2020)
Polio and coxsackie replication organelles (ROs) start as tubules that transform into DMVs, which are enwrapped with more tubules to form multilamellar structures at later stages of infection (Limpens et al, 2011; Belov et al, 2012)
Summary
On entry into the host cell, the viral genome is released, and replication–transcription complexes (RTCs) are assembled that drive viral genome replication and expression of viral proteins. While NPC1 mediates transport of low-density lipoprotein (LDL)– derived cholesterol from late endosomes/lysosomes to the ER, STARD3 transports newly synthesized cholesterol in the opposite direction, from the ER to the endosome (Wilhelm et al, 2017) It is, hard to envisage a role for STARD3 as an LTP that enriches DMVs with endosomal sterol, and a recent study screening a CRISPR library for proteins required for SARS-CoV-2 infection found that neither endosomal STARD3 nor one of its ER-localized binding partners, MOSPD2 (Di Mattia et al, 2018), mediates viral infection or virus-induced cell death (Schneider et al, 2020). The functional significance of this peroxisome association with DMVs is not yet known, but mechanisms for the prevention of oxidative damage to viral RNA or for peroxisome-mediated lipid metabolism in viral replication were proposed (Cortese et al, 2020)
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