title: Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of ubiquitinated proteins induced by prostaglandin J2 without reducing its neurotoxicity.
abstract: The mechanisms implicated in the aggregation of ubiquitinated proteins detected in neurodegenerative disorders remain elusive. We report that prostaglandin J2 (PGJ2), an endogenous product of inflammation, up-regulates sequestosome 1/p62 in a time- and dose-dependent manner in human neuroblastoma SK-N-SH cells. We previously demonstrated that prostaglandins of the J2 series inhibit ubiquitin hydrolases, such as UCH-L1. Herein, we show that sequestosome 1/p62 is co-localized with ubiquitinated proteins and the ubiquitin hydrolase UCH-L1 in cytoplasmic aggregates induced by PGJ2. Preventing sequestosome 1/p62 up-regulation by RNA interference abolishes the aggregation but not the accumulation of ubiquitinated proteins or PGJ2 cytotoxicity. Sequestosome 1/p62 is known to bind poly-ubiquitinated proteins through its ubiquitin-associated domain. Our data support the notion that sequestosome 1/p62 up-regulation under stress conditions contributes to the "sequestration" of poly-ubiquitinated proteins into aggregates. However, the overwhelming accumulation of ubiquitinated proteins, rather than their aggregation, is likely to be an important contributor to PGJ2 cytotoxicity.
authors.affiliation: Department of Biological Sciences, Hunter College of City University of New York, 695 Park Avenue, New York, NY 10021, USA.
authors.forename: Zhiyou
authors.initials: Z
authors.lastname: Wang
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueiredo-Pereira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000071456:Sequestosome-1 Protein; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C482860:UCHL1 protein, human; D025801:Ubiquitin; C037112:9-deoxy-delta-9-prostaglandin D2; D043222:Ubiquitin Thiolesterase; D015230:Prostaglandin D2