RT Journal Article
SR Electronic
T1 Host specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.21.508960
DO 10.1101/2022.09.21.508960
A1 Brian V. Tsu
A1 Rimjhim Agarwal
A1 Nandan S. Gokhale
A1 Jessie Kulsuptrakul
A1 Andrew P. Ryan
A1 Lennice K. Castro
A1 Christopher M. Beierschmitt
A1 Elizabeth A. Turcotte
A1 Elizabeth J. Fay
A1 Russell E. Vance
A1 Jennifer L. Hyde
A1 Ram Savan
A1 Patrick S. Mitchell
A1 Matthew D. Daugherty
YR 2022
UL http://biorxiv.org/content/early/2022/09/22/2022.09.21.508960.abstract
AB Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including SARS-CoV-2, cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8’s ability to sense coronavirus 3CLpros, and instead enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intra-species variation in inflammasome-mediated viral sensing and immunopathology.Competing Interest StatementThe authors have declared no competing interest.