Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology

Abstract

Expansion of polyglutamine (polyQ) tract may cause protein misfolding and aggregation that lead to cytotoxicity and neurodegeneration, but the underlying mechanism remains to be elucidated. We applied ataxin-3 (Atx3), a polyQ tract-containing protein, as a model to study sequestration of normal cellular proteins. We found that the aggregates formed by polyQ-expanded Atx3 sequester its interacting partners, such as P97/VCP and ubiquitin conjugates, into the protein inclusions through specific interactions both in vitro and in cells. Moreover, this specific sequestration impairs the normal cellular function of P97 in down-regulating neddylation. However, expansion of polyQ tract in Atx3 does not alter the conformation of its surrounding regions and the interaction affinities with the interacting partners, although it indeed facilitates misfolding and aggregation of the Atx3 protein. Thus, we propose a loss-of-function pathology for polyQ diseases that sequestration of the cellular essential proteins via specific interactions into inclusions by the polyQ aggregates causes dysfunction of the corresponding proteins, and consequently leads to neurodegeneration.

Aggregation of Polyglutamine-expanded Ataxin 7 Protein Specifically Sequesters Ubiquitin-specific Protease 22 and Deteriorates Its Deubiquitinating Function in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex

“…We discovered, for the first time, that the inclusions or aggregates of polyQ-expanded Atx7 specifically sequester USP22, as in the case of polyQ-expanded Atx3 aggregates, which specifically sequester P97/VCP and ubiquitin conjugates (35). It has also been reported that GCN5 is present in the nuclear inclusions of polyQ-expanded Atx7 in a SCA7 astrocyte model (14).…”

“…The Generality and Individuality of polyQ Diseases-Our previous work has demonstrated that polyQ-expanded Atx3 specifically sequesters P97/VCP and influences its function in down-regulating neddylation and proposed a hijacking model for the cytotoxicity and neurodegeneration caused by polyQexpanded proteins (35). Here we report that polyQ-expanded Atx7 sequesters USP22 into aggregates or inclusions through a specific interaction that impairs the function of the DUBm in deubiquitinating H2Bub.…”

“…A Mutation in the ZnF Domain of Atx7 Disrupts Its Interaction with and Sequestration of USP22-Our previous study indicated that specific interaction is important for the sequestration of its interacting partners by polyQ proteins (33,35). We proposed that the sequestration of USP22 by Atx7 EPQ is also closely associated with their interaction.…”

“…Recently, we revealed that aggregation of polyQ-expanded ataxin 3 (Atx3) specifically sequesters ubiquitin chains and P97/ VCP into inclusions and impairs the normal function of P97/ VCP (35). We investigated the effects of polyQ expansion in Atx7 on USP22 and found that polyQ-expanded Atx7 specifically sequesters USP22 into aggregates or inclusions and reduces the deubiquitination level of histone H2Bub.…”

TDP‐35 sequesters TDP‐43 into cytoplasmic inclusions through binding with RNA

“…We have also revealed that TDP-35 sequesters normal full-length TDP-43 into inclusions in cells, and poly(A)-containing RNAs play a critical role in their association. Thus, we propose that this sequestration mediated by RNA is associated with the TDP-43 proteinopathy and potentially with neurodegeneration, as in the case of the polyQ-expanded proteins that sequester cellular essential interacting partners into inclusions and lead to a loss-of-function pathology [33].…”