RT Journal Article
SR Electronic
T1 Anti-apoptotic BH3-only proteins inhibit Bak-dependent apoptosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.24.499430
DO 10.1101/2022.07.24.499430
A1 Ruehl, Sebastian
A1 Guy, Clifford S.
A1 Li, Zhenrui
A1 Yang, Mao
A1 Moldoveanu, Tudor
A1 Green, Douglas R.
YR 2022
UL http://biorxiv.org/content/early/2022/07/24/2022.07.24.499430.abstract
AB Bcl-2 family proteins regulate induction of intrinsic apoptosis through initiating mitochondrial outer membrane permeabilization (MOMP). Activation of the MOMP effectors Bax and Bak is controlled by interplay levels 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 two Bcl-2 family proteins, BNIP5 and Bcl-G, as inhibitors of Bak, but not Bax induced apoptosis. BNIP5 was able to block 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 domains of BNIP5 and Bcl-G act as a selective Bak activators, while not inhibiting anti-apoptotic proteins. This led to increased binding of activated Bak to Mcl-1, which prevented apoptosis engagement, identifying BNIP5 and Bcl-G as anti-apoptotic BH3-only proteins.Competing Interest StatementD.R.G. consults for Inzen Therapeutics and Ventus Therapeutics. All other authors declare no competing interests