HSP105 interacts with GRP78 and GSK3 and promotes ER stress-induced caspase-3 activation

Gordon P. Meares, Anna A. Zmijewska, Richard S Jope

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)347-358
Number of pages12
JournalCellular Signalling
Volume20
Issue number2
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Unfolded Protein Response
Caspase 3
Cell Death
Apoptosis
Endoplasmic Reticulum Stress
Protein Folding
Heat-Shock Proteins
Neurodegenerative Diseases
DNA Damage
Cell Survival
Proteins

Keywords

  • Apoptosis
  • ER stress
  • GRP78
  • GSK3
  • HSP105
  • UPR

ASJC Scopus subject areas

  • Cell Biology

Cite this

HSP105 interacts with GRP78 and GSK3 and promotes ER stress-induced caspase-3 activation. / Meares, Gordon P.; Zmijewska, Anna A.; Jope, Richard S.

In: Cellular Signalling, Vol. 20, No. 2, 01.02.2008, p. 347-358.

Research output: Contribution to journalArticle

Meares, Gordon P. ; Zmijewska, Anna A. ; Jope, Richard S. / HSP105 interacts with GRP78 and GSK3 and promotes ER stress-induced caspase-3 activation. In: Cellular Signalling. 2008 ; Vol. 20, No. 2. pp. 347-358.
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