beta-Arrestins facilitate ubiquitin-dependent degradation of apoptosis signal-regulating kinase 1 (ASK1) and attenuate H2O2-induced apoptosis.
beta-Arrestins are ubiquitously expressed proteins that play important roles in receptor desensitization, endocytosis, proteosomal degradation, apoptosis and signaling. It has been reported that beta-Arrestin2 acts as a scaffold by directly interacting with the JNK3 isoform and recruiting MKK4 and the apoptosis-signaling kinase-1 (ASK1). Here, we report a novel function of beta-Arrestins in regulating H(2)O(2)-induced apoptosis. Our study demonstrates that beta-Arrestins physically associate with C-terminal domain of ASK1, and moreover, both over-expression and RNA interference (RNAi) experiments indicate that beta-Arrestins down-regulate ASK1 protein. In detail, beta-Arrestin-induced reduction of ASK1 protein is due to ubiquitination and proteasome-dependent degradation of ASK1 in response to association of beta-Arrestins and ASK1. Upon H(2)O(2) stimulation, the protein binding between beta-Arrestins and ASK1 increases and ASK1 degradation is expedited. In consequence, beta-Arrestins prevent ASK1-JNK signaling and as a result attenuate H(2)O(2)-induced apoptosis. Structurally, C-terminal domain of ASK1 is essential for beta-Arrestins and ASK1 association. We also found that CHIP is required for beta-Arrestins-induced ASK1 degradation, which suggested that beta-Arrestins function as a scaffold of ASK1 and CHIP, leading to CHIP-mediated ASK1 degradation. All these findings indicate that beta-Arrestins play a negative regulatory role in H(2)O(2)-induced apoptosis signaling through associating with ASK1 and CHIP and facilitating ASK1 degradation, which provides a new insight for analyzing the effects of beta-Arrestins on protecting cells from oxidative stress-induced apoptosis.
Zhang
Zhengping
Z
Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing, Jiangsu, PR China.
Hao
Jiaying
J
Zhao
Zhihui
Z
Ben
Peiling
P
Fang
Fang
F
Shi
Lijun
L
Gao
Yanhong
Y
Liu
Junhong
J
Wen
Chuanjun
C
Luo
Lan
L
Yin
Zhimin
Z
D017209:Apoptosis / Q000187:drug effects*; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000071557:beta-Arrestins; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019390:Arrestins; D025801:Ubiquitin; D000071557:beta-Arrestins; D006861:Hydrogen Peroxide; D044767:Ubiquitin-Protein Ligases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D046988:Proteasome Endopeptidase Complex