Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:6.3.2.19 (
ubiquitin-protein ligase
)
799
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Mutations in Cu/Zn superoxide dismutase (
SOD1
) cause autosomal dominant amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease with no effective treatment. Despite ample evidence indicating involvement of mutation-induced
SOD1
protein misfolding and aggregation in ALS pathogenesis, the molecular mechanisms that control cellular management of misfolded, aggregation-prone
SOD1
mutant proteins remain unclear. Here, we report that parkin, an E3
ubiquitin-protein ligase
which is linked to Parkinson's disease, is a novel regulator of cellular defense against toxicity induced by ALS-associated
SOD1
mutant proteins. We find that parkin mediates K63-linked polyubiquitination of
SOD1
mutants in cooperation with the UbcH13/Uev1a E2 enzyme and promotes degradation of these misfolded
SOD1
proteins by the autophagy-lysosome system. In response to strong proteotoxic stress associated with proteasome impairment, parkin promotes sequestration of misfolded and aggregated
SOD1
proteins to form perinuclear aggresomes, regulates positioning of lysosomes around misfolded
SOD1
aggresomes, and facilitates aggresome clearance by autophagy. Our findings reveal parkin-mediated cytoprotective mechanisms against misfolded
SOD1
toxicity and suggest that enhancing parkin-mediated cytoprotection may provide a novel therapeutic strategy for treating ALS.
...
PMID:Parkin Protects Against Misfolded SOD1 Toxicity by Promoting Its Aggresome Formation and Autophagic Clearance. 2656 99
Cu, Zn superoxide dismutase
(
SOD1
) is one of the genes implicated in the devastating neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Although the precise mechanisms of
SOD1
mutant (
SOD1
mut
)-induced motoneuron toxicity are still unclear, defects in
SOD1
proteostasis are known to have a critical role in ALS pathogenesis. We previously reported that the
SOD1
mut
adopts a conformation that exposes a Derlin-1-binding region (DBR) and that DBR-exposed
SOD1
interacts with Derlin-1, leading to motoneuron death. We also found that an environmental change,
i.e.
zinc depletion, induces a conformational change in WT
SOD1
(
SOD1
WT
) to the DBR-exposed conformation, suggesting the presence of an equilibrium state between the DBR-masked and DBR-exposed states even with
SOD1
WT
Here, we conducted a high-throughput screening based on time-resolved FRET to further investigate the
SOD1
WT
conformational change, and we used a genome-wide siRNA screen to search for regulators of
SOD1
proteostasis. This screen yielded 30 candidate genes that maintained an absence of the DBR-exposed
SOD1
WT
conformation. Among these genes was one encoding DDB1- and CUL4-associated factor 4 (DCAF4), a substrate receptor of the E3
ubiquitin-protein ligase
complex. Of note, we found that DCAF4 mediates the ubiquitination of an ALS-associated protein and autophagy receptor, optineurin (OPTN), and facilitates autophagic degradation of DBR-exposed
SOD1
. In summary, our screen identifies DCAF4 as being required for proper proteostasis of DBR-exposed
SOD1
, which may have potential relevance for the development of therapies for managing ALS.
...
PMID:Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu,Zn-superoxide dismutase. 3201 91
