The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis

被引：64

作者：

Balasubramanian, Arumugam ^{[1
,2
]}

Hsu, Alan Y. ^{[1
,2
]}

Ghimire, Laxman ^{[1
,2
]}

Tahir, Muhammad ^{[1
,2
,3
]}

Devant, Pascal ^{[4
,5
]}

Fontana, Pietro ^{[6
]}

Du, Gang ^{[6
]}

Liu, Xing ^{[7
]}

Fabin, Dang ^{[8
]}

Kambara, Hiroto ^{[1
,2
]}

Xie, Xuemei ^{[1
,2
]}

Liu, Fei ^{[1
,2
]}

Hasegawa, Tomoya ^{[1
,2
]}

Xu, Rong ^{[1
,2
]}

Yu, Hongbo ^{[9
]}

Chen, Mei ^{[10
]}

Kolakowski, Steven ^{[10
]}

Trauger, Sunia ^{[10
]}

Larsen, Martin Rossel ^{[3
]}

Wei, Wenyi ^{[8
]}

Wu, Hao ^{[6
]}

Kagan, Jonathan C. ^{[4
,5
]}

Lieberman, Judy ^{[7
]}

Luo, Hongbo R. ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Harvard Canc Ctr, Dana Farber, Dept Pathol, Enders Res Bldg, Room 811, Boston, MA 02115 USA

[2] Boston Childrens Hosp, Dept Lab Med, Enders Res Bldg,Room 811, Boston, MA 02115 USA

[3] Univ Southern Denmark, Biomed Mass Spectrometry & Syst Biol, Odense, Denmark

[4] Boston Childrens Hosp, Div Gastroenterol, 300 Longwood Ave, Boston, MA 02115 USA

[5] Harvard Med Sch, 300 Longwood Ave, Boston, MA 02115 USA

[6] Harvard Med Sch, Boston Childrens Hosp, Dept Biol Chem & Mol Pharmacol, Program Cellular & Mol Med, Boston, MA 02115 USA

[7] Harvard Med Sch, Boston Childrens Hosp, Dept Pediat, Program Cellular & Mol Med, Boston, MA 02115 USA

[8] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA

[9] VA Boston Healthcare Syst, Dept Pathol & Lab Med, 1400 VFW Pkwy, West Roxbury, MA 02132 USA

[10] Harvard Univ, Harvard Ctr Mass Spectrometry, Cambridge, MA 02138 USA

来源：

SCIENCE IMMUNOLOGY | 2024年 / 9卷 / 94期

关键词：

FATTY-ACID SYNTHASE; PROTEIN PALMITOYLATION; INFLAMMATORY CASPASES; CELL-DEATH; GSDMD; MECHANISM; DRIVEN;

D O I：

10.1126/sciimmunol.adn1452

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 Cys(191)/Cys(192) (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-1 beta 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.

引用

页数：19

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