Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis

被引：149

作者：

Miao, Rui ^{[1
,2
]}

Jiang, Cong ^{[3
,4
]}

Chang, Winston Y. ^{[1
,2
]}

Zhang, Haiwei ^{[1
,2
]}

An, Jinsu ^{[1
,2
]}

Ho, Felicia ^{[1
,2
]}

Chen, Pengcheng ^{[4
]}

Zhang, Han ^{[3
,4
]}

Junqueira, Caroline ^{[1
,2
,5
]}

Amgalan, Dulguun ^{[6
,7
]}

Liang, Felix G. ^{[6
,7
]}

Zhang, Junbing ^{[8
,9
]}

Evavold, Charles L. ^{[10
]}

Hafner-Bratkovic, Iva ^{[11
,12
,13
,14
,15
]}

Zhang, Zhibin ^{[1
,2
,16
]}

Fontana, Pietro ^{[1
,17
]}

Xia, Shiyu ^{[1
,17
]}

Waldeck-Weiermair, Markus ^{[18
]}

Pan, Youdong ^{[19
,20
]}

Michel, Thomas ^{[18
]}

Bar-Peled, Liron

Wu, Hao ^{[1
,17
]}

Kagan, Jonathan C.

Kitsis, Richard N. ^{[6
,7
]}

Zhang, Peng ^{[3
]}

Liu, Xing ^{[4
]}

Lieberman, Judy ^{[1
,2
]}

机构：

[1] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA

[2] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[3] Tongji Univ, Shanghai Pulm Hosp, Sch Med, Dept Thorac Surg, Shanghai 200433, Peoples R China

[4] Chinese Acad Sci, Shanghai Inst Immun & Infect, Key Lab RNA Sci & Engn, Shanghai 200031, Peoples R China

[5] Fundacao Oswaldo Cruz, Inst Rene Rachou, BR-30190009 Belo Horizonte, MG, Brazil

[6] Albert Einstein Coll Med, Wilf Family Cardiovasc Res Inst, Dept Med, New York, NY 10461 USA

[7] Albert Einstein Coll Med, Wilf Family Cardiovasc Res Inst, Dept Cell Biol, New York, NY 10461 USA

[8] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02129 USA

[9] Harvard Med Sch, Dept Med, Boston, MA 02129 USA

[10] MIT & Harvard, Ragon Inst Mass Gen, Cambridge, MA 02139 USA

[11] Boston Childrens Hosp, Div Gastroenterol, Boston, MA 02115 USA

[12] Harvard Med Sch, Boston, MA 02115 USA

[13] Univ Ljubljana, Natl Inst Chem, Dept Synthet Biol & Immunol, Ljubljana 1000, Slovenia

[14] Univ Ljubljana, EN FIST Ctr Excellence, Ljubljana 1000, Slovenia

[15] Univ Ljubljana, Fac Med, Ljubljana 1000, Slovenia

[16] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA

[17] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[18] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Cardiovasc Div, Boston, MA 02115 USA

[19] Harvard Med Sch, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA

[20] Harvard Med Sch, Brigham & Womens Hosp, Harvard Skin Dis Res Ctr, Boston, MA 02115 USA

来源：

IMMUNITY | 2023年 / 56卷 / 11期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

CARDIOLIPIN; CASPASE-11; APOPTOSIS; IDENTIFICATION; CLEAVAGE; RELEASE; PROTEIN; TRIGGER; ROLES; CELLS;

D O I：

10.1016/j.immuni.2023.10.004

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial mem-branes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane poten-tial, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasome activation of mitochondrial damage, pyroptosis, and inflammatory cytokine release were suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiency in a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrial damage plays a critical role in pyroptosis.

引用

页码：2523 / 2541.e8

页数：28

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