Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of ubiquitinated proteins induced by prostaglandin J2 without reducing its neurotoxicity.
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.
Wang
Zhiyou
Z
Department of Biological Sciences, Hunter College of City University of New York, 695 Park Avenue, New York, NY 10021, USA.
Figueiredo-Pereira
Maria E
ME
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
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