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USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis.

ABSTRACT: Accumulation of ubiquitinated proteins is cytotoxic, but cells inactivate these cytotoxicities by inducing aggresome formation. We found that ubiquitin-specific protease 10 (USP10) inhibits ubiquitinated protein-induced apoptosis by inducing aggresome formation. USP10 interacted with the ubiquitin receptor p62 and the interaction augmented p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby cooperatively inhibiting apoptosis. We provide evidence that USP10/p62-induced protein aggregates inhibit proteasome activity, which increases the amount of ubiquitinated proteins and promotes aggresome formation. USP10 induced aggresomes containing ?-synuclein, a pathogenic protein in Parkinson disease, in cultured cells. In Parkinson disease brains, USP10 was colocalized with ?-synuclein in the disease-linked aggresome-like inclusion Lewy bodies, suggesting that USP10 inhibits ?-synuclein-induced neurotoxicity by promoting Lewy body formation. Collectively, these findings suggest that USP10 is a critical factor to control protein aggregation, aggresome formation, and cytotoxicity in protein-aggregation-related diseases.

SUBMITTER: Takahashi M

PROVIDER: S-EPMC6249355 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis.

Takahashi Masahiko M Kitaura Hiroki H Kakita Akiyoshi A Kakihana Taichi T Katsuragi Yoshinori Y Nameta Masaaki M Zhang Lu L Iwakura Yuriko Y Nawa Hiroyuki H Higuchi Masaya M Komatsu Masaaki M Fujii Masahiro M

iScience 20181105

Accumulation of ubiquitinated proteins is cytotoxic, but cells inactivate these cytotoxicities by inducing aggresome formation. We found that ubiquitin-specific protease 10 (USP10) inhibits ubiquitinated protein-induced apoptosis by inducing aggresome formation. USP10 interacted with the ubiquitin receptor p62 and the interaction augmented p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby cooperatively inhibiting apoptosis. We provide evidence that USP10/p62-induce ...[more]

PMID: 30469013

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Project description:BackgroundUbiquitin-proteasome-system-mediated clearance of misfolded proteins is essential for cells to maintain proteostasis and reduce the proteotoxicity caused by these aberrant proteins. When proteasome activity is inadequate, ubiquitinated proteins are sorted into perinuclear aggresomes, which is a significant defense mechanism employed by cells to combat insufficient proteasome activity, hence mitigating the proteotoxic crisis. It has been demonstrated that phosphorylation of SQSTM1 is crucial in regulating misfolded protein aggregation and autophagic degradation. Although SQSTM1 S403 phosphorylation is essential for the autophagic degradation of ubiquitinated proteins, its significance in proteasome inhibition-induced aggresome formation is yet unknown. Herein, we investigated the influence of SQSTM1 S403 phosphorylation on the aggresome production of ubiquitinated proteins during proteasome suppression.MethodsWe examined the phosphorylation levels of SQSTM1 S403 or T269/S272 in cells after treated with proteasome inhibitors or/and autophagy inhibitors, by western blot and immunofluorescence. We detected the accumulation and aggresome formation of ubiquitinated misfolded proteins in cells treated with proteasome inhibition by western blot and immunofluorescence. Furthermore, we used SQSTM1 phosphorylation-associated kinase inhibitors and mutant constructs to confirm the regulation of different SQSTM1 phosphorylation in aggresome formation. We examined the cell viability using CCK-8 assay.ResultsHerein, we ascertained that phosphorylation of SQSTM1 S403 did not enhance the autophagic degradation of ubiquitinated proteins during proteasome inhibition. Proteasome inhibition suppresses the phosphorylation of SQSTM1 S403, which facilitated the aggresome production of polyubiquitinated proteins. Interestingly, we found proteasome inhibition-induced SQSTM1 T269/S272 phosphorylation inhibits the S403 phosphorylation. Suppressing S403 phosphorylation rescues the defective aggresome formation and protects cells from cell death caused by unphosphorylated SQSTM1 (T269/S272).ConclusionsThis study shows that inhibition of SQSTM1 S403 phosphorylation facilitates the aggresome formation of ubiquitinated proteins during proteasome dysfunction. SQSTM1 T269/S272 phosphorylation inhibits the S403 phosphorylation, boosting the aggresome formation of ubiquitinated protein and shielding cells from proteotoxic crisis.

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USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis.

Publications

USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis.

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