Inhibition of BAK-mediated Apoptosis by the BH3-only Protein BNIP5

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2024 Oct 15

PMID 39406920

Authors

Sebastian Ruhl

Zhenrui Li

Shagun Srivastava

Luigi Mari

Clifford S Guy

Mao Yang

Tudor Moldoveanu

Douglas R Green

Affiliations

Soon will be listed here.

Abstract

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.

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