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Mechanism and Regulation of Gasdermin-Mediated Cell Death.

ABSTRACT: The innate immune system senses and responds to pathogens and endogenous damage through supramolecular protein complexes known as inflammasomes. Cytosolic inflammasome sensor proteins trigger inflammasome assembly on detection of infection and danger. Assembled inflammasomes activate a cascade of inflammatory caspases, which process procytokines and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores that lead to cytokine release and/or programmed lytic cell death, called pyroptosis. In this review, we provide a primer on pyroptosis and focus on its executioner, the GSDM protein family. In addition to inflammasome-mediated GSDMD pore formation, we describe recently discovered GSDMD activation by caspase-8 and elastase in Yersinia-infected macrophages and aging neutrophils, respectively, and GSDME activation by apoptotic caspases. Finally, we discuss strategies that host cells and pathogens use to restrict GSDMD pore formation, in addition to therapeutics targeting the GSDM family.

SUBMITTER: Xia S

PROVIDER: S-EPMC7050592 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Mechanism and Regulation of Gasdermin-Mediated Cell Death.

Xia Shiyu S Hollingsworth Louis Robert LR Wu Hao H

Cold Spring Harbor perspectives in biology 20200302 3

The innate immune system senses and responds to pathogens and endogenous damage through supramolecular protein complexes known as inflammasomes. Cytosolic inflammasome sensor proteins trigger inflammasome assembly on detection of infection and danger. Assembled inflammasomes activate a cascade of inflammatory caspases, which process procytokines and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores that lead to cytokine release and/or programmed lytic cell death, called pyroptosis. In this ...[more]

PMID: 31451512

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Project description:Human coronavirus 229E (HCoV-229E) is associated with upper respiratory tract infections and generally causes mild respiratory symptoms. HCoV-229E infection can cause cell death, but the molecular pathways that lead to virus-induced cell death as well as the interplay between viral proteins and cellular cell death effectors remain poorly characterized for HCoV-229E. Studying how HCoV-229E and other common cold coronaviruses interact with and affect cell death pathways may help to understand its pathogenesis and compare it to that of highly pathogenic coronaviruses. Here, we report that the main protease (Mpro) of HCoV-229E can cleave gasdermin D (GSDMD) at two different sites (Q29 and Q193) within its active N-terminal domain to generate fragments that are now unable to cause pyroptosis, a form of lytic cell death normally executed by this protein. Despite GSDMD cleavage by HCoV-229E Mpro, we show that HCoV-229E infection still leads to lytic cell death. We demonstrate that during virus infection caspase-3 cleaves and activates gasdermin E (GSDME), another key executioner of pyroptosis. Accordingly, GSDME knockout cells show a significant decrease in lytic cell death upon virus infection. Finally, we show that HCoV-229E infection leads to increased lytic cell death levels in cells expressing a GSDMD mutant uncleavable by Mpro (GSDMD Q29A+Q193A). We conclude that GSDMD is inactivated by Mpro during HCoV-229E infection, preventing GSDMD-mediated cell death, and point to the caspase-3/GSDME axis as an important player in the execution of virus-induced cell death. In the context of similar reported findings for highly pathogenic coronaviruses, our results suggest that these mechanisms do not contribute to differences in pathogenicity among coronaviruses. Nonetheless, understanding the interactions of common cold-associated coronaviruses and their proteins with the programmed cell death machineries may lead to new clues for coronavirus control strategies.

Dataset Information

Mechanism and Regulation of Gasdermin-Mediated Cell Death.

Publications

Mechanism and Regulation of Gasdermin-Mediated Cell Death.

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