BCL-2-family protein tBID can act as a BAX-like effector of apoptosis

被引：118

作者：

Flores-Romero, Hector ^{[1
,2
,3
]}

Hohorst, Lisa ^{[1
,2
]}

John, Malina ^{[3
]}

Albert, Marie-Christine ^{[4
,5
]}

King, Louise E. ^{[1
,2
]}

Beckmann, Laura ^{[2
,6
,7
]}

Szabo, Tamas ^{[8
]}

Hertlein, Vanessa ^{[3
,13
]}

Luo, Xu ^{[9
,10
]}

Villunger, Andreas ^{[8
,11
,12
]}

Frenzel, Lukas P. ^{[2
,6
,7
]}

Kashkar, Hamid ^{[4
,5
]}

Garcia-Saez, Ana J. ^{[1
,2
,3
]}

机构：

[1] Univ Cologne, Inst Genet, Cologne, Germany

[2] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany

[3] Eberhard Karls Univ Tubingen, Interfac Inst Biochem, Tubingen, Germany

[4] Univ Cologne, Univ Hosp Cologne, Fac Med, Inst Mol Immunol, Cologne, Germany

[5] Univ Cologne, Univ Hosp Cologne, Fac Med, Ctr Mol Med Cologne CMMC, Cologne, Germany

[6] Univ Hosp Cologne, Dept & Internal Med, Cologne, Germany

[7] Univ Hosp Cologne, Ctr Integrated Oncol ABCD, Cologne, Germany

[8] Med Univ Innsbruck, Bioctr, Div Dev Immunol, Innsbruck, Austria

[9] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, ME USA

[10] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA

[11] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria

[12] Ludwig Boltzmann Inst Rare & Undiagnosed Dis, Vienna, Austria

[13] Children Canc Res Inst CCRI, Vienna, Austria

来源：

EMBO JOURNAL | 2022年 / 41卷 / 02期

基金：

奥地利科学基金会; 欧洲研究理事会;

关键词：

apoptosis; BCL-2; proteins; mitochondrial permeabilization; pore formation; PORE-FORMING PROTEINS; CYTOCHROME-C RELEASE; BCL-2; FAMILY; CONFORMATIONAL-CHANGES; BH3; DOMAIN; MEMBRANE; BCL-X(L); OLIGOMERIZATION; MITOCHONDRIA; ACTIVATION;

D O I：

10.15252/embj.2021108690

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

During apoptosis, the BCL-2-family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti-apoptotic BCL-2 members. Here, we report that tBID can also mediate mitochondrial permeabilization by itself, resulting in release of cytochrome c and mitochondrial DNA, caspase activation and apoptosis even in absence of BAX and BAK. This previously unrecognized activity of tBID depends on helix 6, homologous to the pore-forming regions of BAX and BAK, and can be blocked by pro-survival BCL-2 proteins. Importantly, tBID-mediated mitochondrial permeabilization independent of BAX and BAK is physiologically relevant for SMAC release in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to lack of active BAX and BAK. Our findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL-2 proteins, with implications for anti-bacterial immunity and cancer therapy.

引用

页数：17

共 76 条

[1] BID-dependent release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella [J].