The E2 ubiquitin-conjugating enzyme HIP2 is a crucial regulator of quality control against mutant SOD1 proteotoxicity
- Authors
- Tak, Yeong Jin; Kang, Seongman
- Issue Date
- 1-Feb-2022
- Publisher
- ELSEVIER
- Keywords
- ALS; SOD1; Protein aggregates; HIP2; UPS; Proteotoxicity
- Citation
- BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v.1868, no.2
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
- Volume
- 1868
- Number
- 2
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/139383
- DOI
- 10.1016/j.bbadis.2021.166316
- ISSN
- 0925-4439
- Abstract
- Mutations in superoxide dismutase 1 (SOD1) leading to the formation of intracellular protein aggregates cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by a selective degeneration of motor neurons. The ALS-linked mutant SOD1 emerged as a possible target for ubiquitin-proteasome system (UPS)-mediated degradation. We aimed to elucidate the role of huntingtin interaction protein 2 (HIP2), an E2 ubiquitin-conjugating enzyme, in the proteotoxicity of mutant SOD1 aggregates. We found that HIP2 interacts with mutant SOD1, but not wild-type SOD1, and is upregulated in response to mutant SOD1 expression. Upregulation of HIP2 protein was observed in the spinal cord of 16-week-old SOD1-G93A transgenic mice. HIP2 further modified mutant SOD1 proteins via K48-linked polyubiquitination and degraded mutant SOD1 proteins through the UPS. Upregulation of HIP2 protected cells from mutant SOD1-induced toxicity. Taken together, our findings demonstrate that HIP2 is a crucial regulator of quality control against the proteotoxicity of mutant SOD1. Our results suggest that modulating HIP2 may represent a novel therapeutic strategy for the treatment of ALS.
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Collections - College of Life Sciences and Biotechnology > Division of Life Sciences > 1. Journal Articles
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