The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis
Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys191/Cys192 (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1β release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Science immunology - 9(2024), 94 vom: 12. Apr., Seite eadn1452 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Balasubramanian, Arumugam [VerfasserIn] |
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| Links: |
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| Themen: |
GSDMD protein, human |
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| Anmerkungen: |
Date Completed 15.04.2024 Date Revised 16.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Feb 21;:. - PMID 36865189 Citation Status MEDLINE |
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| doi: |
10.1126/sciimmunol.adn1452 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM37019716X |
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| 500 | |a UpdateOf: bioRxiv. 2023 Feb 21;:. - PMID 36865189 | ||
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| 520 | |a Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys191/Cys192 (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1β release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases | ||
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| 700 | 1 | |a Hsu, Alan Y |e verfasserin |4 aut | |
| 700 | 1 | |a Ghimire, Laxman |e verfasserin |4 aut | |
| 700 | 1 | |a Tahir, Muhammad |e verfasserin |4 aut | |
| 700 | 1 | |a Devant, Pascal |e verfasserin |4 aut | |
| 700 | 1 | |a Fontana, Pietro |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xing |e verfasserin |4 aut | |
| 700 | 1 | |a Fabin, Dang |e verfasserin |4 aut | |
| 700 | 1 | |a Kambara, Hiroto |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Xuemei |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Hasegawa, Tomoya |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Hongbo |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Kolakowski, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Trauger, Sunia |e verfasserin |4 aut | |
| 700 | 1 | |a Larsen, Martin Røssel |e verfasserin |4 aut | |
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| 700 | 1 | |a Kagan, Jonathan C |e verfasserin |4 aut | |
| 700 | 1 | |a Lieberman, Judy |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Hongbo R |e verfasserin |4 aut | |
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