title: Ubiquitin-like sequence in ASK1 plays critical roles in the recognition and stabilization by USP9X and oxidative stress-induced cell death.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagai
authors.forename: Takuya
authors.initials: T
authors.lastname: Noguchi
authors.forename: Kengo
authors.initials: K
authors.lastname: Homma
authors.forename: Kazumi
authors.initials: K
authors.lastname: Katagiri
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: 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
chemical_list: 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