RRC ID 81388
Author Takahashi M, Kitaura H, Kakita A, Kakihana T, Katsuragi Y, Onodera O, Iwakura Y, Nawa H, Komatsu M, Fujii M.
Title USP10 Inhibits Aberrant Cytoplasmic Aggregation of TDP-43 by Promoting Stress Granule Clearance.
Journal Mol Cell Biol
Abstract TAR DNA-binding protein 43 (TDP-43) is a causative factor of amyotrophic lateral sclerosis (ALS). Cytoplasmic TDP-43 aggregates in neurons are a hallmark pathology of ALS. Under various stress conditions, TDP-43 localizes sequentially to two cytoplasmic protein aggregates, namely, stress granules (SGs) first and then aggresomes. Accumulating evidence suggests that delayed clearance of TDP-43-positive SGs is associated with pathological TDP-43 aggregates in ALS. We found that ubiquitin-specific protease 10 (USP10) promotes the clearance of TDP-43-positive SGs in cells treated with proteasome inhibitor, thereby promoting the formation of TDP-43-positive aggresomes, and the depletion of USP10 increases the amount of insoluble TDP-35, a cleaved product of TDP-43, in the cytoplasm. TDP-35 interacted with USP10 in an RNA-binding-dependent manner; however, impaired RNA binding of TDP-35 reduced the localization in SGs and aggresomes and induced USP10-negative TDP-35 aggregates. Immunohistochemistry showed that most of the cytoplasmic TDP-43/TDP-35 aggregates in the neurons of ALS patients were USP10 negative. Our findings suggest that USP10 inhibits aberrant aggregation of TDP-43/TDP-35 in the cytoplasm of neuronal cells by promoting the clearance of TDP-43/TDP-35-positive SGs and facilitating the formation of TDP-43/TDP-35-positive aggresomes.
Volume 42(3)
Pages e0039321
Published 2022-3-17
DOI 10.1128/MCB.00393-21
PMID 35007165
PMC PMC8929388
MeSH Amyotrophic Lateral Sclerosis* / genetics Cytoplasm / metabolism Cytoplasmic Granules / metabolism DNA-Binding Proteins / metabolism Humans RNA / metabolism Stress Granules Ubiquitin Thiolesterase / metabolism
Resource
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)