Publication

Hspb1 facilitates erk-mediated phosphorylation and degradation of bim to attenuate endoplasmic reticulum stress-induced apoptosis

Kennedy, Donna
; 
Mnich, Katarzyna
; 
Oommen, Deepu
; 
Chakravarthy, Reka
; 
Almeida-Souza, Leonardo
; 
Krols, Michiel
; 
Saveljeva, Svetlana
; 
Doyle, Karen M.
; 
Gupta, Sanjeev
; 
Timmerman, Vincent
... show 3 more
Repository DOI
Publication Date
2017-08-31
Keywords
heat-shock proteins, cytochrome-c release, bh3-only protein, pc12 cells, membrane permeabilization, proteasomal degradation, mitochondrial-membrane, apaf-1 apoptosome, bcl-2 proteins, hsp27
Type
Article
Downloads
Show all metadata
Citation
Kennedy, Donna; Mnich, Katarzyna; Oommen, Deepu; Chakravarthy, Reka; Almeida-Souza, Leonardo; Krols, Michiel; Saveljeva, Svetlana; Doyle, Karen; Gupta, Sanjeev; Timmerman, Vincent; Janssens, Sophie; Gorman, Adrienne M; Samali, Afshin (2017). Hspb1 facilitates erk-mediated phosphorylation and degradation of bim to attenuate endoplasmic reticulum stress-induced apoptosis. Cell Death and Disease 8 ,
Abstract
BIM, a pro-apoptotic BH3-only protein, is a key regulator of the intrinsic (or mitochondrial) apoptosis pathway. Here, we show that BIM induction by endoplasmic reticulum (ER) stress is suppressed in rat PC12 cells overexpressing heat shock protein B1 (HSPB1 or HSP27) and that this is due to enhanced proteasomal degradation of BIM. HSPB1 and BIM form a complex that immunoprecipitates with p-ERK1/2. We found that HSPB1-mediated proteasomal degradation of BIM is dependent on MEK-ERK signaling. Other studies have shown that several missense mutations in HSPB1 cause the peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, which is associated with nerve degeneration. Here we show that cells overexpressing CMT-related HSPB1 mutants exhibited increased susceptibility to ER stress-induced cell death and high levels of BIM. These findings identify a novel function for HSPB1 as a negative regulator of BIM protein stability leading to protection against ER stress-induced apoptosis, a function that is absent in CMT-associated HSPB1 mutants.
Funder
Publisher
Springer Nature
Publisher DOI
10.1038/cddis.2017.408
Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland
cbn
Collections
Externally hosted open access publications with University of Galway authors (2)