1. PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates
- Author
-
Hong-Wei Yue, Lei-Lei Jiang, Hong-Yu Hu, S. J. Zhang, and Jun-Ye Hong
- Subjects
Amyloid ,Proteasome Endopeptidase Complex ,Huntingtin ,Science ,Intracellular Space ,Amyloidogenic Proteins ,Protein aggregation ,Transfection ,Protein Aggregation, Pathological ,Article ,Inclusion bodies ,Protein Aggregates ,Protein Domains ,medicine ,Humans ,Ataxin-3 ,Inclusion Bodies ,Huntingtin Protein ,Multidisciplinary ,Chemistry ,Neurodegeneration ,Neurodegenerative Diseases ,HSP40 Heat-Shock Proteins ,medicine.disease ,Cell biology ,Repressor Proteins ,Co-chaperone ,Mechanisms of disease ,HEK293 Cells ,Proteostasis ,Solubility ,Ataxin ,Proteolysis ,Medicine ,Protein folding ,Peptides ,Molecular Chaperones ,Signal Transduction - Abstract
Polyglutamine (polyQ) expansion of proteins can trigger protein misfolding and amyloid-like aggregation, which thus lead to severe cytotoxicities and even the respective neurodegenerative diseases. However, why polyQ aggregation is toxic to cells is not fully elucidated. Here, we took the fragments of polyQ-expanded (PQE) ataxin-7 (Atx7) and huntingtin (Htt) as models to investigate the effect of polyQ aggregates on the cellular proteostasis of endogenous ataxin-3 (Atx3), a protein that frequently appears in diverse inclusion bodies. We found that PQE Atx7 and Htt impair the cellular proteostasis of Atx3 by reducing its soluble as well as total Atx3 level but enhancing formation of the aggregates. Expression of these polyQ proteins promotes proteasomal degradation of endogenous Atx3 and accumulation of its aggregated form. Then we verified that the co-chaperone HSJ1 is an essential factor that orchestrates the balance of cellular proteostasis of Atx3; and further discovered that the polyQ proteins can sequester HSJ1 into aggregates or inclusions in a UIM domain-dependent manner. Thereby, the impairment of Atx3 proteostasis may be attributed to the sequestration and functional loss of cellular HSJ1. This study deciphers a potential mechanism underlying how PQE protein triggers proteinopathies, and also provides additional evidence in supporting the hijacking hypothesis that sequestration of cellular interacting partners by protein aggregates leads to cytotoxicity or neurodegeneration.
- Published
- 2021