Hsp70 promotes TNF-mediated apoptosis by binding IKK gamma and impairing NF-kappa B survival signaling.
The major heat shock protein, Hsp70, can protect against cell death by directly interfering with mitochondrial apoptosis pathways. However, Hsp70 also sensitizes cells to certain apoptotic stimuli like TNF. Little is known about how Hsp70 enhances apoptosis. We demonstrate here that Hsp70 promotes TNF killing by specifically binding the coiled-coil domain of I kappa B kinase gamma (IKK gamma) to inhibit IKK activity and consequently inhibit NF-kappa B-dependent antiapoptotic gene induction. An IKK gamma mutant, which interacts with Hsp70, competitively inhibits the Hsp70-IKK gamma interaction and relieves heat-mediated NF-kappa B suppression. Depletion of Hsp70 expression with RNA interference rescues TNF-mediated cell death. Although TNF may or may not be sufficient to trigger apoptosis on its own, TNF-triggered apoptosis was initiated or made worse when Hsp70 expression increased to high levels to disrupt NF-kappa B signaling. These results provide significant novel insights into the molecular mechanism for the pro-apoptotic behavior of Hsp70 in death-receptor-mediated cell death.
Ran
Ruiqiong
R
Department of Neurology, University of Cincinnati, Cincinnati, Ohio 45267, USA. ranr@email.uc.edu
Lu
Aigang
A
Zhang
Lu
L
Tang
Yang
Y
Zhu
Hongyan
H
Xu
Huichun
H
Feng
Yuxin
Y
Han
Chun
C
Zhou
Guoping
G
Rigby
Alan C
AC
Sharp
Frank R
FR
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase; D016328:NF-kappa B / Q000502:physiology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human