Inhibition of BAK-mediated apoptosis by the BH3-only protein BNIP5

被引：2

作者：

Ruhl, Sebastian ^{[1
,4
]}

Li, Zhenrui ^{[1
]}

Srivastava, Shagun ^{[2
]}

Mari, Luigi ^{[1
]}

Guy, Clifford S. ^{[1
]}

Yang, Mao ^{[1
]}

Moldoveanu, Tudor ^{[2
,3
]}

Green, Douglas R. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

[2] UAMS Coll Med, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA

[3] St Jude Childrens Res Hosp, Dept Struct Biol, Memphis, TN 38105 USA

[4] T3 Pharmaceuticals, Allschwil, Switzerland

来源：

CELL DEATH AND DIFFERENTIATION | 2025年 / 32卷 / 02期

关键词：

PROSURVIVAL BCL-2; BH3; DOMAINS; BCL-X(L); MITOCHONDRIA; ACTIVATION; ABSENCE; MODEL; MCL-1; AKT;

D O I：

10.1038/s41418-024-01386-3

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：

BCL-2 family proteins regulate apoptosis by initiating mitochondrial outer membrane permeabilization (MOMP). Activation of the MOMP effectors BAX and BAK is controlled by the interplay of anti-apoptotic BCL-2 proteins (e.g., MCL-1) and pro-apoptotic BH3-only proteins (e.g., BIM). Using a genome-wide CRISPR-dCas9 transactivation screen we identified BNIP5 as an inhibitor of BAK-, but not BAX-induced apoptosis. BNIP5 blocked BAK activation in different cell types and in response to various cytotoxic therapies. The BH3 domain of BNIP5 was both necessary and sufficient to block BAK activation. Mechanistically, the BH3 domain of BNIP5 acts as a selective BAK activator, but a poor de-repressor of complexes between BAK and pro-survival BCL-2 family proteins. By promoting the binding of activated BAK to MCL-1 or BCL-xL, BNIP5 inhibits apoptosis when BAX is absent. Based on our observations, BNIP5 can act functionally as an anti-apoptotic BH3-only protein.

引用

页码：320 / 336

页数：17

共 55 条

[1] Peptides from human BNIP5 and PXT1 and non-native binders of pro-apoptotic BAK can directly activate or inhibit BAK-mediated membrane permeabilization [J].

Aguilar, Fiona ;

Yu, Stacey ;

Grant, Robert A. ;

Swanson, Sebastian ;

Ghose, Dia ;

Su, Bonnie G. ;

Sarosiek, Kristopher A. ;

Keating, Amy E. .

STRUCTURE, 2023, 31 (03) :265-+

[2] Redefining the BH3 Death Domain as a 'Short Linear Motif' [J].

Aouacheria, Abdel ;

Combet, Christophe ;

Tompa, Peter ;

Hardwick, J. Marie .

TRENDS IN BIOCHEMICAL SCIENCES, 2015, 40 (12) :736-748

[3] Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria [J].

Arnoult, D ;

Bartle, LM ;

Skaletskaya, A ;

Poncet, D ;

Zamzami, N ;

Park, PU ;

Sharpe, J ;

Youle, RJ ;

Goldmacher, VS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (21) :7988-7993

[4] Msp1 cooperates with the proteasome for extraction of arrested mitochondrial import intermediates [J].

Basch, Marion ;

Wagner, Mirjam ;

Rolland, Stephane ;

Carbonell, Andres ;

Zeng, Rachel ;

Khosravi, Siavash ;

Schmidt, Andreas ;

Aftab, Wasim ;

Imhof, Axel ;

Wagener, Johannes ;

Conradt, Barbara ;

Wagener, Nikola .

MOLECULAR BIOLOGY OF THE CELL, 2020, 31 (08) :753-767

[5] Structure of detergent-activated BAK dimers derived from the inert monomer [J].

Birkinshaw, Richard W. ;

Iyer, Sweta ;

Lio, Daisy ;

Luo, Cindy S. ;

Brouwer, Jason M. ;

Miller, Michelle S. ;

Robin, Adeline Y. ;

Uren, Rachel T. ;

Dewson, Grant ;

Kluck, Ruth M. ;

Colman, Peter M. ;

Czabotar, Peter E. .

MOLECULAR CELL, 2021, 81 (10) :2123-+

[6] Bak Core and Latch Domains Separate during Activation, and Freed Core Domains Form Symmetric Homodimers [J].

Brouwer, Jason M. ;

Westphal, Dana ;

Dewson, Grant ;

Robin, Adeline Y. ;

Uren, Rachel T. ;

Bartolo, Ray ;

Thompson, Geoff V. ;

Colman, Peter M. ;

Kluck, Ruth M. ;

Czabotar, Peter E. .

MOLECULAR CELL, 2014, 55 (06) :938-946

[7] An interconnected hierarchical model of cell death regulation by the BCL-2 family [J].

Chen, Hui-Chen ;

Kanai, Masayuki ;

Inoue-Yamauchi, Akane ;

Tu, Ho-Chou ;

Huang, Yafen ;

Ren, Decheng ;

Kim, Hyungjin ;

Takeda, Shugaku ;

Reyna, Denis E. ;

Chan, Po M. ;

Ganesan, Yogesh Tengarai ;

Liao, Chung-Ping ;

Gavathiotis, Evripidis ;

Hsieh, James J. ;

Cheng, Emily H. .

NATURE CELL BIOLOGY, 2015, 17 (10) :1270-+

[8] Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment [J].

Chen, Xufeng ;

Glytsou, Christina ;

Zhou, Hua ;

Narang, Sonali ;

Reyna, Denis E. ;

Lopez, Andrea ;

Sakellaropoulos, Theodore ;

Gong, Yixiao ;

Kloetgen, Andreas ;

Yap, Yoon Sing ;

Wang, Eric ;

Gavathiotis, Evripidis ;

Tsirigos, Aristotelis ;

Tibes, Raoul ;

Aifantis, Iannis .

CANCER DISCOVERY, 2019, 9 (07) :890-909

[9] VDAC2 enables BAX to mediate apoptosis and limit tumor development [J].

Chin, Hui San ;

Li, Mark X. ;

Tan, Iris K. L. ;

Ninnis, Robert L. ;

Reljic, Boris ;

Scicluna, Kristen ;

Dagley, Laura F. ;

Sandow, Jarrod J. ;

Kelly, Gemma L. ;

Samson, Andre L. ;

Chappaz, Stephane ;

Khaw, Seong L. ;

Chang, Catherine ;

Morokoff, Andrew ;

Brinkmann, Kerstin ;

Webb, Andrew ;

Hockings, Colin ;

Hall, Cathrine M. ;

Kueh, Andrew J. ;

Ryan, Michael T. ;

Kluck, Ruth M. ;

Bouillet, Philippe ;

Herold, Marco J. ;

Gray, Daniel H. D. ;

Huang, David C. S. ;

van Delft, Mark F. ;

Dewson, Grant .

NATURE COMMUNICATIONS, 2018, 9

[10] Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic Chemotherapy [J].

Chonghaile, Triona Ni ;

Sarosiek, Kristopher A. ;

Thanh-Trang Vo ;

Ryan, Jeremy A. ;

Tammareddi, Anupama ;

Moore, Victoria Del Gaizo ;

Deng, Jing ;

Anderson, Kenneth C. ;

Richardson, Paul ;

Tai, Yu-Tzu ;

Mitsiades, Constantine S. ;

Matulonis, Ursula A. ;

Drapkin, Ronny ;

Stone, Richard ;

DeAngelo, Daniel J. ;

McConkey, David J. ;

Sallan, Stephen E. ;

Silverman, Lewis ;

Hirsch, Michelle S. ;

Carrasco, Daniel Ruben ;

Letai, Anthony .

SCIENCE, 2011, 334 (6059) :1129-1133

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