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. 2023 Jan 11;21(3):178–194. doi: 10.1038/s41579-022-00839-1

Fig. 1. SARS-CoV-2 strategies to minimize host detection.

Fig. 1

SARS-CoV-2 enters into a host cell by binding angiotensin-converting enzyme 2 (ACE2) on the cell surface, a process that can be facilitated by transmembrane protease serine 2 (TMPRSS2), which provides proteolytic cleavage of the viral spike (S) protein to promote virus–host fusion. Following internalization of the viral particle, the capped and polyadenylated genomic viral RNA is released into the cytoplasm where it can be directly translated (stage 1). Initial translation of viral genomic RNA results in the production of the ORF1a and ORF1ab polyproteins (pp1a and pp1ab) that are subsequently processed by viral proteases to form the replicase and non-structural proteins (Nsps; depicted in yellow) necessary to establish replication organelles (ROs). Nsp3 and Nsp4 mediate the modification of endoplasmic reticulum (ER) membranes into convoluted membranes (CM) and double-membrane vesicles (DMVs) that make up ROs, whereas Nsp6 forms a zippered molecular tether between ROs and the ER that enables the flow of lipids (stage 2). Nascent viral RNA is modified by Nsp enzymes (depicted in blue) to mimic host transcripts and minimize the ability of the cell to induce a defence. First, Nsp13 (a 5′ RNA triphosphatase) removes the phosphate from the 5′ end of the viral RNA. This is followed by the transfer of a guanosine monophosphate to the 5′ end by Nsp12 (a guanylyltransferase) to yield the cap core. Subsequently, Nsp14 (an N7-methyltransferase) and Nsp16 (a 2′-O-methyltransferase) assisted by the Nsp10 capping cofactor catalyse the final methylation steps necessary to complete the viral cap (stage 3). As viral replication proceeds, negative-sense RNA (−ssRNA) and double-stranded RNA (dsRNA) intermediates are sequestered inside ROs to prevent host detection. In parallel, the positive-sense, single-stranded genomic and subgenomic RNAs (+ssRNA) needed for translation of viral proteins and de novo virion assembly are chaperoned from the replication organelles. As replication intensifies, viral RNAs accumulate outside of ROs, and are masked and/or minimized by the SARS-CoV-2 nucleocapsid protein (N) and/or Nsp15, depicted in orange (stage 4).