BRSK2 is regulated by ER stress in protein level and involved in ER stress-induced apoptosis.
The accumulation of unfolded protein in lumen of the endoplasmic reticulum (ER) triggers a cell stress response called ER stress, which induces the transcriptional up-regulation of a number of proteins, including molecular chaperones and folding enzymes, the global inhibition of protein synthesis, and the activation of apoptotic pathways. The molecular mechanism underlying the apoptotic response has remained largely elusive. AMP activated protein kinase (AMPK) has been implicated in ER stress-induced apoptosis through its role in attenuating ER stress. BRSK2 (brain selective kinase 2, also known as SAD-A) is a serine/threonine kinase of the AMPK family. Here, we demonstrate that the BRSK2 protein levels are significantly down-regulated in response to ER stress in PANC-1 and HeLa cells. Furthermore, we also observed that ER stress induces endogenous BRSK2 to localize to the ER. Importantly, knockdown of endogenous BRSK2 expression enhances ER stress-mediated apoptosis in cells while over express BRSK2 in wild type or kinase-dead type both reduce the apoptosis. BRSK2 knockdown increases the transcription of CHOP and the levels of cleaved caspase-3 in cells in response to ER stress while over expression of BRSK2 decrease CHOP mRNA and levels of cleaved caspase-3. Taken together, our findings demonstrate ER stress may reduce BRSK2 protein and change BRSK2 subcellular localization, which in turn alleviate ER stress-induced apoptosis.
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai, PR China.
Yingli
Y
Wang
Bo
B
Wan
Dawei
D
Li
Jun
J
Zhou
Ruwei
R
Li
Meirong
M
Bai
Fang
F
Chen
Long
L
Yu
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051742:Transcription Factor CHOP / Q000096:biosynthesis
C497249:DDIT3 protein, human; D012333:RNA, Messenger; D051742:Transcription Factor CHOP; C507732:Brsk2 protein, human; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3