PolyQ‐expanded huntingtin and ataxin‐3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin

What is it about?

Protein misfolding and aggregation are closely associated with the pathogenesis of neurodegenerative diseases. The aggregated proteins are commonly accumulated with the components of ubiquitin (Ub)-proteasome system in the inclusions, but how protein aggregates sequester these Ub-related proteins remains unknown. Using pathogenic polyQ proteins huntingtin (Htt) and ataxin-3 (Atx3) as models, the molecular mechanism underlying the sequestration of Ub adaptors by polyQ-expanded proteins was investigated in detail. The results show that polyQ-expanded Htt-N552 and Atx3 sequester endogenous Ub adaptors, human RAD23 homolog B (hHR23B) and ubiquilin 2 (UBQLN2), depending on the UBA domains of Ub adaptors and ubiquitination of the aggregated proteins. Moreover, these polyQ aggregates reduce the protein level of xeroderma pigmentosum group C (XPC) through sequestering hHR23B and cutting down its available quantity, and thus affect the normal function of hHR23B in stabilizing XPC. The finding demonstrates that polyQ-expanded proteins sequester Ub adaptors or other Ub-related proteins into aggregates or inclusions through ubiquitination of the pathogenic proteins. This study sheds light on the molecular mechanism underlying the sequestration of Ub-related proteins by polyQ-expanded proteins and the formation of Ub-positive inclusions in different neurodegenerative diseases.

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