title: HSP105 interacts with GRP78 and GSK3 and promotes ER stress-induced caspase-3 activation.
abstract: Stress of the endoplasmic reticulum (ER stress) is caused by the accumulation of misfolded proteins, which occurs in many neurodegenerative diseases. ER stress can lead to adaptive responses or apoptosis, both of which follow activation of the unfolded protein response (UPR). Heat shock proteins (HSP) support the folding and function of many proteins, and are important components of the ER stress response, but little is known about the role of one of the major large HSPs, HSP105. We identified several new partners of HSP105, including glycogen synthase kinase-3 (GSK3), a promoter of ER stress-induced apoptosis, and GRP78, a key component of the UPR. Knockdown of HSP105 did not alter UPR signaling after ER stress, but blocked caspase-3 activation after ER stress. In contrast, caspase-3 activation induced by genotoxic stress was unaffected by knockdown of HSP105, suggesting ER stress-specificity in the apoptotic action of HSP105. However, knockdown of HSP105 did not alter cell survival after ER stress, but instead diverted signaling to a caspase-3-independent cell death pathway, indicating that HSP105 is necessary for apoptotic signaling after UPR activation by ER stress. Thus, HSP105 appears to chaperone the responses to ER stress through its interactions with GRP78 and GSK3, and without HSP105 cell death following ER stress proceeds by a non-caspase-3-dependent process.
authors: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
authors: Gordon P
authors: GP
authors: Meares
authors: Anna A
authors: AA
authors: Zmijewska
authors: Richard S
authors: RS
authors: Jope
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D050957:HSP110 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D050957:HSP110 Heat-Shock Proteins; C000717247:HSPA5 protein, human; C097205:HSPH1 protein, human; D006360:Heat-Shock Proteins; C490783:Hsp105 protein, mouse; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3