Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor.
At the neuropathological level, Parkinson's disease (PD) is characterized by the accumulation of misfolded proteins, which can trigger the unfolded protein response (UPR). UCH-L1 is a component of ubiquitin proteasome system (UPS). It is reported that the loss of its function will impair ubiquitin proteasome system and cause toxicity to cells. But its mechanism has not been illustrated. In this study, we detected the protein expression of Bip/Grp78 and the spliced form of XBP-1 to examine the activation of unfolded protein response after SK-N-SH cells being treated with LDN-57444, a UCH-L1 inhibitor which could inhibit UCH-L1 hydrolase activity. Our data showed that UCH-L1 inhibitor was able to cause cell death through the apoptosis pathway by decreasing the activity of ubiquitin proteasome system and increasing the levels of highly ubiquitinated proteins, both of which can activate unfolded protein response. There is a lot of evidence that unfolded protein response is activated as a protective response at the early stage of the stress; this protective response can switch to a pro-apoptotic response when the stress persists. In this study, we demonstrated this switch by detecting the upregulation of CHOP/Gadd153. Taken together, our data indicated that the apoptosis induced by UCH-L1 inhibitor may be triggered by the activation of endoplasmic reticulum stress (ERS). Moreover, we provide a new cell model for studying the roles of UCH-L1 in Parkinson's disease.
Tan
Yu-Yan
YY
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China. rabbit82@gmail.com
Zhou
Hai-Yan
HY
Wang
Zhi-Quan
ZQ
Chen
Sheng-Di
SD
D017398:Alternative Splicing / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D018832:Molecular Chaperones / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors*; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007211:Indoles; C525086:LDN 57444; D018832:Molecular Chaperones; D010091:Oximes; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C482860:UCHL1 protein, human; D025801:Ubiquitin; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex