Parkin Suppresses Unfolded Protein Stress-induced Cell Death through Its E3 Ubiquitin-protein Ligase Activity*

By Y. Imai, Mariko Soda, R. Takahashi. Journal of Biological Chemistry, 2000

783 citations recorded by the source corpus.

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 NH2-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.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/977ae942a46d7931e411a91c3ebe026524364c0d

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Citations in the corpus

Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword? (2007, positive): “Interestingly, expression of Parkin is induced by ER stress, and neuronal cells overexpressing Parkin are resistant to ER stress (55).”
PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy (2010, background): “In 2000, we and others found that dysfunction of an E3 ubiquitin ligase (Imai et al., 2000; Shimura et al., 2000; Zhang et al., 2000) termed Parkin causes autosomal recessive juvenile Parkinsonism (Kitada et al., 1998).”
Alpha-synuclein and neurodegenerative diseases (2001, background): “Parkin functions as a ubiquitin ligase, and the known mutations are believed to lead to a loss of its functio”
Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities (2008, background): “Overexpression of wild-type Parkin suppresses cell death that is induced by several ER-stress-inducing pharmacological agents and by α-synuclein — the principal component of Lewy bodies, representing the pathopneumonic lesion of Parkinson's diseas”
Roles of CHOP/GADD153 in endoplasmic reticulum stress (2004, background): “103 Parkin is induced by ER stress, and overexpression of parkin confers resistance to both ER stress and mutant α -synuclein-induced toxicity”
CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation (2004, background): “Unfolded PAELR is a substrate of the E3 ubiquitin ligase parkin and accumulation of non-ubiquitinated PAELR in the endoplasmic reticulum (ER) of dopaminergic neurons induces ER stress, leading to neurodegeneration (19).”
Orchestrating the unfolded protein response in health and disease. (2002, background): “Overexpression of Parkin suppresses cell death associated with ER stress (60).”
The roles of intracellular protein-degradation pathways in neurodegeneration (2006, background): “These include parkin, an E3 ligase in which autosomal recessive loss-of-function mutations cause P”
Expression of A53T Mutant But Not Wild-Type α-Synuclein in PC12 Cells Induces Alterations of the Ubiquitin-Dependent Degradation System, Loss of Dopamine Release, and Autophagic Cell Death (2001, background): “Whether -synuclein itself is degraded by the proteasome is controversial (Bennett et al., 1999; Ancolio et al., 2000; Imai et al., 2000; Rideout et al., 2001).”