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) |