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-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 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 noncaspase-3-dependent process.

Intermediate frequency magnetic fields generated by an induction heating (IH) cooktop do not affect genotoxicities and expression of heat shock proteins

“…In response to heat shock stress, the expression of phosphorylated Hsp27 was upregulated (Wang et al 2006; 408C lowest positive temperature), and Hsp27, 70 and 105 translocated to the nucleus, consistent with previous investigations (Lepock et al 2001, Meares et al 2008. In contrast, exposure to IF magnetic fields at 6.05 mT rms did not induce any alteration of the expression of phosphorylated Hsp27 or translocation of Hsp27, 70 and 105.…”

VCP Mutations Causing Frontotemporal Lobar Degeneration Disrupt Localization of TDP-43 and Induce Cell Death

“…Proteasome malfunction has been shown to activate the caspase cascade and, eventually, apoptotic cell death (69). Activation of ER stress and the unfolded protein response has been shown previously to induce the caspase cascade (63,73,74). We describe a specific induction of ER stress involving an increase in the molecular chaperone GRP78.…”

ER stress-mediated apoptosis induced by celastrol in cancer cells and important role of glycogen synthase kinase-3β in the signal network

“…It is now well known that GSK3 β functions in diverse cellular processes including proliferation, differentiation, motility and survival and is involved in energy metabolism, neuronal cell development, body pattern formation and ER stress. 32, 33, 34, 35 Moreover, aberrant regulation of GSK3 β has been implicated in a range of human pathologies including neoplastic transformation and tumor development. 36, 37 Especially, GSK3 β has been recognized as an important modulator of apoptosis.…”