Ubiquitin-like sequence in ASK1 plays critical roles in the recognition and stabilization by USP9X and oxidative stress-induced cell death.
Ubiquitination is an important posttranslational modification that regulates various cellular processes, including signal transduction. However, physiological roles of ubiquitination in the regulation of MAPK pathways are poorly understood. Here, we identified the deubiquitinating enzyme USP9X as a binding partner of ASK1 that mediates oxidative stress-induced cell death through activation of the JNK and p38 MAPK pathways. In the recognition of ubiquitin by deubiquitinating enzymes, the importance of a tandem glycine-glycine sequence in the ubiquitin C terminus has been suggested. Interestingly, ASK1 contains six amino acids identical to the ubiquitin C terminus (LRLRGG), and the GG sequence of ASK1 was required for the USP9X-ASK1 interaction. We also found that USP9X interacted with oxidative stress-activated ASK1 and prevented it from undergoing ubiquitin-dependent degradation. In USP9X-deficient cells, oxidative stress-induced JNK activation and subsequent cell death were reduced. These results demonstrate that USP9X-dependent stabilization of activated ASK1 plays a crucial role in oxidative stress-induced cell death.
Nagai
Hiroaki
H
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Global Center of Excellence Program and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Noguchi
Takuya
T
Homma
Kengo
K
Katagiri
Kazumi
K
Takeda
Kohsuke
K
Matsuzawa
Atsushi
A
Ichijo
Hidenori
H
D000595:Amino Acid Sequence; D017209:Apoptosis; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D054875:Ubiquitination
C506234:USP9X protein, human; D025801:Ubiquitin; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D043222:Ubiquitin Thiolesterase