Endogenous Bok is stable at the endoplasmic reticulum membrane and does not mediate proteasome inhibitor-induced apoptosis.

Autor: Bonzerato CG; Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States., Keller KR; Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States., Schulman JJ; Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States., Gao X; Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States., Szczesniak LM; Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States., Wojcikiewicz RJH; Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States.
Jazyk: angličtina
Zdroj: Frontiers in cell and developmental biology [Front Cell Dev Biol] 2022 Dec 19; Vol. 10, pp. 1094302. Date of Electronic Publication: 2022 Dec 19 (Print Publication: 2022).
DOI: 10.3389/fcell.2022.1094302
Abstrakt: Controversy surrounds the cellular role of the Bcl-2 family protein Bok. On one hand, it has been shown that all endogenous Bok is bound to inositol 1,4,5-trisphosphate receptors (IP 3 Rs), while other data suggest that Bok can act as a pro-apoptotic mitochondrial outer membrane permeabilization mediator, apparently kept at very low and non-apoptotic levels by efficient proteasome-mediated degradation. Here we show that 1) endogenous Bok is expressed at readily-detectable levels in key cultured cells (e.g., mouse embryonic fibroblasts and HCT116 cells) and is not constitutively degraded by the proteasome, 2) proteasome inhibitor-induced apoptosis is not mediated by Bok, 3) endogenous Bok expression level is critically dependent on the presence of IP 3 Rs, 4) endogenous Bok is rapidly degraded by the ubiquitin-proteasome pathway in the absence of IP 3 Rs at the endoplasmic reticulum membrane, and 5) charged residues in the transmembrane region of Bok affect its stability, ability to interact with Mcl-1, and pro-apoptotic activity when over-expressed. Overall, these data indicate that endogenous Bok levels are not governed by proteasomal activity (except when IP 3 Rs are deleted) and that while endogenous Bok plays little or no role in apoptotic signaling, exogenous Bok can mediate apoptosis in a manner dependent on its transmembrane domain.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Bonzerato, Keller, Schulman, Gao, Szczesniak and Wojcikiewicz.)
Databáze: MEDLINE
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