The E2 ubiquitin-conjugating enzyme HIP2 is a crucial regulator of quality control against mutant SOD1 proteotoxicity

Yeong Jin Tak, Seongman Kang

    Research output: Contribution to journalArticlepeer-review

    7 Citations (Scopus)

    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.

    Original languageEnglish
    Article number166316
    JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
    Volume1868
    Issue number2
    DOIs
    Publication statusPublished - 2022 Feb 1

    Bibliographical note

    Publisher Copyright:
    © 2021 Elsevier B.V.

    Keywords

    • ALS
    • HIP2
    • Protein aggregates
    • Proteotoxicity
    • SOD1
    • UPS

    ASJC Scopus subject areas

    • Molecular Medicine
    • Molecular Biology

    Fingerprint

    Dive into the research topics of 'The E2 ubiquitin-conjugating enzyme HIP2 is a crucial regulator of quality control against mutant SOD1 proteotoxicity'. Together they form a unique fingerprint.

    Cite this