Molecular Biomedicine | Cleavage of the selective autophagy receptor SQSTM1/p62 by the SARS-CoV-2 main protease NSP5 prevents the autophagic degradation of viral membrane proteins


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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) global pandemic. Omicron, a new variant of SARS-CoV-2, has the characteristics of strong transmission and pathogenicity, short incubation period, and rapid onset progression, and has spread rapidly around the world. The high replication rate and intracellular accumulation of SARS-CoV-2 are remarkable, but the underlying molecular mechanisms remain unclear. Autophagy acts as a conservative cellular defence mechanism against invading pathogens. Here, authors provide evidence that the main protease of SARS-CoV-2, NSP5, effectively cleaves the selective autophagy receptor p62. NSP5 targets p62 for cleavage at glutamic acid 354 and thus abolishes the capacity of p62 to mediate selective autophagy. It was further shown that p62 specifically interacted with ubiquitinated SARS-CoV-2 M, the viral membrane protein, to promote its autophagic degradation. In the presence of NSP5, p62-mediated autophagic degradation of the M protein was inhibited. The cleaved products of p62 also cannot facilitate the degradation of the M protein. Collectively, their findings reveal that p62 is a novel host target of SARS-CoV-2 NSP5 and suggest that selective autophagy targets viruses and potential strategies by which the virus evades autophagic clearance. Their results may provide new ideas for the development of anti-COVID-19 drugs based on autophagy and NSP5.

Here, p62 was identified as a host cleavage target of NSP5 at Gln354, which impaired p62 as a receptor of selective autophagy. p62 interacted with SARS-CoV-2 capsid membrane protein M and targeted it for autophagic degradation. These data uncovered that SARS-CoV-2 impairs selective autophagy in host cells, which can be exploited for the development of antiviral drugs against COVID-19.

Schematic illustration of SARS-CoV-2 NSP5 cleavage on p62 attenuating p62-mediated autophagic degradation of virus and capsid M protein