Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu,Zn-superoxide dismutase
Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 295, Issue: 10, Page: 3148-3158
2020
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Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu/Zn superoxide dismutase.
J Biol Chem. 2020 Feb 3; Authors: Homma K, Takahashi H, Tsuburaya N, Naguro I, Fujisawa T, Ichijo H PubMed: 32014991 Submit Comment
Article Description
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.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0021925817495160; http://dx.doi.org/10.1074/jbc.ra119.010239; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85081045791&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/32014991; https://linkinghub.elsevier.com/retrieve/pii/S0021925817495160; https://dx.doi.org/10.1074/jbc.ra119.010239
Elsevier BV
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