Fungal gasdermin-like proteins are controlled by proteolytic cleavage.

Autor:	Clavé C; UMR 5095, CNRS, Non-self Recognition in Fungi, Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, 33077 Bordeaux, France; corinne.clave@ibgc.cnrs.fr asen.daskalov@u-bordeaux.fr., Dyrka W; Politechnika Wrocławska, Wydział Podstawowych Problemów Techniki, Katedra Inżynierii Biomedycznej, 50-370 Wrocław, Poland., Turcotte EA; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720., Granger-Farbos A; UMR 5095, CNRS, Non-self Recognition in Fungi, Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, 33077 Bordeaux, France., Ibarlosa L; UMR 5095, CNRS, Non-self Recognition in Fungi, Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, 33077 Bordeaux, France., Pinson B; UMR 5095, CNRS, Genetics of Metabolic Pathways, Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, 33077 Bordeaux, France., Vance RE; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.; HHMI, University of California, Berkeley, CA 94720.; Immunotherapeutics and Vaccine Research Initiative, University of California, Berkeley, CA 94720.; Cancer Research Laboratory, University of California, Berkeley, CA 94720., Saupe SJ; UMR 5095, CNRS, Non-self Recognition in Fungi, Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, 33077 Bordeaux, France., Daskalov A; UMR 5095, CNRS, Non-self Recognition in Fungi, Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, 33077 Bordeaux, France; corinne.clave@ibgc.cnrs.fr asen.daskalov@u-bordeaux.fr.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Feb 15; Vol. 119 (7).
DOI:	10.1073/pnas.2109418119
Abstrakt:	Gasdermins are a family of pore-forming proteins controlling an inflammatory cell death reaction in the mammalian immune system. The pore-forming ability of the gasdermin proteins is released by proteolytic cleavage with the removal of their inhibitory C-terminal domain. Recently, gasdermin-like proteins have been discovered in fungi and characterized as cell death-inducing toxins in the context of conspecific non-self-discrimination (allorecognition). Although functional analogies have been established between mammalian and fungal gasdermins, the molecular pathways regulating gasdermin activity in fungi remain largely unknown. Here, we characterize a gasdermin-based cell death reaction controlled by the het-Q allorecognition genes in the filamentous fungus Podospora anserina We show that the cytotoxic activity of the HET-Q1 gasdermin is controlled by proteolysis. HET-Q1 loses a ∼5-kDa C-terminal fragment during the cell death reaction in the presence of a subtilisin-like serine protease termed HET-Q2. Mutational analyses and successful reconstitution of the cell death reaction in heterologous hosts ( Saccharomyces cerevisiae and human 293T cells) suggest that HET-Q2 directly cleaves HET-Q1 to induce cell death. By analyzing the genomic landscape of het-Q1 homologs in fungi, we uncovered that the vast majority of the gasdermin genes are clustered with protease-encoding genes. These HET-Q2-like proteins carry either subtilisin-like or caspase-related proteases, which, in some cases, correspond to the N-terminal effector domain of nucleotide-binding and oligomerization-like receptor proteins. This study thus reveals the proteolytic regulation of gasdermins in fungi and establishes evolutionary parallels between fungal and mammalian gasdermin-dependent cell death pathways. Competing Interests: The authors declare no competing interest. (Copyright © 2022 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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