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
Apoptosis Research Centre, Biomedical Sciences, NUI Galway, Galway, Ireland.
Peripheral Neuropathy Research Group, University of Antwerp, Antwerpen, Belgium.
Cell Death Dis. 2017 Aug 31;8(8):e3026. doi: 10.1038/cddis.2017.408.
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.
BIM是一种仅含BH3结构域的促凋亡蛋白，是内源性（或线粒体）凋亡途径的关键调节因子。在此，我们发现，在过表达热休克蛋白B1（HSPB1或HSP27）的大鼠PC12细胞中，内质网（ER）应激诱导的BIM表达受到抑制，这是由于BIM的蛋白酶体降解增强所致。HSPB1和BIM形成一种复合物，可与p-ERK1/2进行免疫沉淀。我们发现，HSPB1介导的BIM蛋白酶体降解依赖于MEK-ERK信号传导。其他研究表明，HSPB1中的几个错义突变会导致周围神经病变——夏科-马里-图斯（CMT）病，该病与神经变性有关。在此我们表明，过表达与CMT相关的HSPB1突变体的细胞对ER应激诱导的细胞死亡更敏感，且BIM水平较高。这些发现确定了HSPB1作为BIM蛋白稳定性的负调节因子的新功能，从而赋予细胞对ER应激诱导的凋亡的保护作用，而CMT相关的HSPB1突变体则缺乏这一功能。
