SARS-CoV-2 papain-like protease inhibits IL-1β maturation and pyroptosis
through disruption of ASC oligomerization and deubiquitination of ASC
Abstract
The perplexing innate immune response induced by SARS-CoV-2 infection
remains inadequate uncovered. Previous studies showed that coronavirus
papain-like protease (PLP) could evade type I interferons mediated
innate immune responses. In this study, we found the inflammasome genes
(NLRP3, NLRP6, PYCARD, IL1B, IL18, TRIM31, FBXL2, MARCH7) were
down-regulated in CD14+ monocytes from COVID-19 patients. Secondly, we
found that SARS-CoV-2 PLP may act on the NLRP3 inflammasome pathway. PLP
may interact with ASC and interrupt ASC oligomerization by reducing the
K48-linked and K63-linked ubiquitination of ASC, so that the excessive
activation of the NLRP3 inflammatory pathway might be inhibited and the
release of IL-1β was blocked. Thirdly, SARS-CoV-2 PLP negatively
regulated the pyroptosis of host cells, which was mediated by caspase-1,
the key regulator of the NLRP3 inflammasome pathway. In general,
SARS-CoV-2 PLP avoids the excessive immune defenses in the early stage
of virus infection, which provides the maximum advantage for virus
replication. These insights uncover the flex function of CoV encoding
proteases. Furthermore, this research may provide a new vision of
COVID-19 epidemic prevention and new possibilities for new therapies.