The regulation of ER stress induced cell death by HSPB1 (hsp27)

Kennedy, Donna
Endoplasmic reticulum (ER) stress is associated with several human pathologies including neurodegenerative disorders. ER stress results in accumulation of unfolded proteins which activates the unfolded protein response (UPR). Heat shock proteins (HSP) are stress-inducible cyto-protective proteins which mediate the heat shock response (HSR). We investigated whether heat shock (HS) preconditioning can block ER stress-induced apoptosis. Treatment of cells with ER stress-inducing drugs caused cell death. Heat shock preconditioning prior to ER stress treatment significantly reduced cell death and reduced levels of the pro-apoptotic protein, BIM. Overexpression of HSPB1 could mimic the effect of HS on expression levels of BIM. We conclude that HS is protective against ER stress-induced cell death, partly through HSPB1-mediated reduction BIM. HSPB1 acts as a suppressor of cell death however its role in ER stress-induced apoptosis has not been elucidated. Using PC12s overexpressing HSPB1 we investigated the molecular mechanism by which HSPB1 protects against ER stress-induced apoptosis and regulates the expression of BIM. Overexpression of HSPB1 reduced ER stress-induced apoptosis. Examination of signalling pathways critical to the regulation of BIM identified HSPB1 as a regulator of the proteasomal degradation of BIM. This was in part due to HSPB1 enhancing phosphor-ERK levels. Moreover knockdown of BIM effectively inhibited the protective effects of HSPB1 highlighting the importance of HPSB1 mediated regulation of BIM in protection against ER stress. Mutations in HSPB1 are associated with Charcot Marie Tooth (CMT) disease, a peripheral neuropathy. We found that cells which overexpress mutant HSPB1 are more sensitive to ER stress-induced apoptosis and have high levels of BIM. Collectively we have identified a novel function for HSPB1 as a regulator of ER stress-induced apoptosis, a function which is lost in HSPB1 CMT associated mutations.
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Attribution-NonCommercial-NoDerivs 3.0 Ireland