Heat shock protein 70 together with its co-chaperone CHIP inhibits TNF-alpha induced apoptosis by promoting proteasomal degradation of apoptosis signal-regulating kinase1.
Inducible heat shock protein70 (HSP70) is one of the most important HSPs for maintenance of cell integrity during normal cellular growth as well as pathophysiological conditions. Apoptosis signal-regulating kinase (ASK) 1, a mammalian MAPKKK, activates the JNK and p38 pathways. Here we report a novel function of HSP70 in regulating TNF-alpha-induced cell apoptosis. Our study demonstrated that HSP70 physically interacted with ASK1 and promoted the ubiquitin-dependent proteasomal degradation of ASK1. CHIP (carboxyl terminus of the HSC70-interacting protein) which acted as a co-chaperone of HSP70 cooperated with HSP70 in regulating ASK1. We also found that TNF-alpha stimulated HSP70/CHIP/ASK1 association and through cooperating with CHIP, HSP70 inhibits TNF-alpha-induced cell apoptosis both in over-expression and RNAi conditions. Structural analysis indicated that C-terminal domain of HSP70 was necessary for ASK1 degradation, and N- terminal domain of ASK1 was essential for its binding to HSP70. All these findings indicated that HSP70 and CHIP association is important for HSP70 in interacting with ASK1. Through forming the complex of HSP70/CHIP/ASK1, HSP70 promotes ASK1 proteasomal degradation and prevents TNF-alpha-induced cell apoptosis.
Gao
Yanhong
Y
Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing, 210046, People's Republic of China.
Han
Cui
C
Huang
Huang
H
Xin
Yinqiang
Y
Xu
Yimiao
Y
Luo
Lan
L
Yin
Zhimin
Z
D017209:Apoptosis; D002460:Cell Line; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000737:chemistry / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054875:Ubiquitination
D018840:HSP70 Heat-Shock Proteins; D014409:Tumor Necrosis Factor-alpha; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D048848:MAP Kinase Kinase Kinase 5; D046988:Proteasome Endopeptidase Complex