Key Points

TRIM21 regulates virus-induced pyroptosis.

ISG12a is required for TRIM21-mediated pyroptosis.

TRIM21 promotes ISG12a mitochondrial migration by ubiquitination of ISG12a.

Visual AbstractAbstract

Pyroptosis is a form of regulated cell death mediated by the gasdermin protein family. During virus infection, cell pyroptosis restricts viral replication. The mechanisms of the tripartite motif (TRIM) protein family and IFN-stimulated genes (ISGs) against viruses have been studied. The role of TRIMs and ISGs in pyroptosis remains unclear. In this study, we show that TRIM21 interacts with ISG12a in viral infection and facilitates its translocation into the mitochondria by promoting its ubiquitination, thereby causing caspase 3 activation. Gasdermin E (GSDME) is specifically cleaved by caspase 3 upon viral infection, releasing the GSDME N-terminal domain, perforating the cell membrane, and causing cell pyroptosis. Our study uncovers a new mechanism of TRIM21 and ISG12a in regulating virus-induced cell pyroptosis.

Footnotes

This work was supported by the National Natural Science Foundation of China Grants 81730064 (H.Z.), 82072269 (H.Z.), and 81571985 (H.Z.) and National Major Science and Technology Projects of China Grant 2017ZX10202201-005 (H.Z.).

M.G. conceived and designed the experiments with W.C., S.C., and S.T., M.G. performed most of the experiments and data analysis with assistance from W.C., S.C., R.T., L.W., Q.L., X.W., Z.W., Y.Z., and D.Y., B.X. performed immunoprecipitations. R.D. prepared tissue sections. C.Z. provided tissue samples. G.L. simulated the interaction between two proteins using bioinformatics methods. H.Z. advised on the project studies and revised the manuscript.

The online version of this article contains supplemental material.

Abbreviations used in this article:

co-IPcoimmunoprecipitationGSDMDgasdermin DGSDMEgasdermin EHCVhepatitis C virusIRFIFN regulatory factorISGIFN-stimulated geneLDHlactate dehydrogenaseMAVSmitochondrial antiviral signalingMOImultiplicity of infectionNDVNewcastle disease virusPIpropidium iodideshRNAshort hairpin RNATRIMtripartite motifVSVvesicular stomatitis virusWTwild typeReceived March 2, 2022.Accepted August 12, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.