Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity.
Autosomal recessive juvenile parkinsonism (AR-JP) is caused by mutations in the parkin gene. Parkin protein is characterized by a ubiquitin-like domain at its NH(2)-terminus and two RING finger motifs and an IBR (in between RING fingers) at its COOH terminus (RING-IBR-RING). Here, we show that Parkin is a RING-type E3 ubiquitin-protein ligase which binds to E2 ubiquitin-conjugating enzymes, including UbcH7 and UbcH8, through its RING-IBR-RING motif. Moreover, we found that unfolded protein stress induces up-regulation of both the mRNA and protein level of Parkin. Furthermore, overexpression of Parkin, but not a set of mutants without the E3 activity, specifically suppressed unfolded protein stress-induced cell death. These findings demonstrate that Parkin is an E3 enzyme and suggest that it is involved in the ubiquitination pathway for misfolded proteins derived from endoplasmic reticulum and contributes to protection from neurotoxicity induced by unfolded protein stresses.
Imai
Y
Y
Laboratory for Motor System Neurodegeneration, RIKEN Brain Science Institute (BSI), Saitama 351-0198, Japan.
Soda
M
M
Takahashi
R
R
D020816:Amino Acid Motifs; D000818:Animals; D016923:Cell Death; D002460:Cell Line; D006801:Humans; D008025:Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D018696:Neuroprotective Agents / Q000378:metabolism; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism; D015854:Up-Regulation
D018696:Neuroprotective Agents; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases; D008025:Ligases