title: The SUMO E3-ligase PIAS1 couples reactive oxygen species-dependent JNK activation to oxidative cell death.
abstract: Human endometrial stromal cells (HESCs) exposed to reactive oxygen species (ROS) mount a hypersumoylation response in a c-Jun N-terminal kinase (JNK)-dependent manner. The mechanism that couples JNK signaling to the small ubiquitin-related modifier (SUMO) pathway and its functional consequences are not understood. We show that ROS-dependent JNK activation converges on the SUMO pathway via PIAS1 (protein inhibitor of activated STAT1). Unexpectedly, PIAS1 knockdown not only prevented ROS-dependent hypersumoylation but also enhanced JNK signaling in HESCs. Conversely, PIAS overexpression increased sumoylation of various substrates, including c-Jun, yet inhibited basal and ROS-dependent JNK activity independently of its SUMO ligase function. Expression profiling demonstrated that PIAS1 knockdown enhances and profoundly modifies the transcriptional response to oxidative stress signals. Using a cutoff of 2-fold change or more, a total of 250 ROS-sensitive genes were identified, 97 of which were not dependent on PIAS1. PIAS1 knockdown abolished the regulation of 43 genes but also sensitized 110 other genes to ROS. Importantly, PIAS1 silencing was obligatory for the induction of several cellular defense genes in response to oxidative stress. In agreement, PIAS1 knockdown attenuated ROS-dependent caspase-3/7 activation and subsequent apoptosis. Thus, PIAS1 determines the level of JNK activity in HESCs, couples ROS signaling to the SUMO pathway, and promotes oxidative cell death.
authors.affiliation: Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, UK.
authors.forename: Beatriz B
authors.initials: BB
authors.lastname: Leitao
authors.forename: Marius C
authors.initials: MC
authors.lastname: Jones
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Brosens
mesh_terms: D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation
chemical_list: C106529:PIAS1 protein, human; D050828:Protein Inhibitors of Activated STAT; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D025841:Small Ubiquitin-Related Modifier Proteins; D048670:MAP Kinase Kinase 4