ArticleMolecular neurobiology2026
USP28 Deficiency is Linked to Impaired Ubiquitin-dependent Proteostasis in Huntington's Disease.
Article in Molecular neurobiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Huntington's disease (HD) is characterized by mutant huntingtin (mHTT) aggregation and impaired proteostasis; however, upstream regulators of ubiquitin system imbalance remain incompletely understood. This study identified the deubiquitinase USP28 as a potential modulator of ubiquitin-dependent proteostasis in HD. Bulk RNA sequencing of R6/2 mouse brain tissues showed reduced USP28 expression compared with wild-type controls. Consistently, USP28 expression decreased in STHdh striatal cells expressing expanded polyQ huntingtin (Q111). HD cells (STHdh-Q111) exhibited increased accumulation of ubiquitinated proteins and altered ubiquitin turnover, consistent with impaired proteostasis. USP28 overexpression attenuated ubiquitinated protein accumulation and reduced mHTT aggregation, whereas a catalytically inactive USP28 mutant showed limited rescue effects. In addition, USP28 depletion was associated with reduced UBR5 levels, while USP28 restoration partially recovered UBR5 expression in a catalytic activity-dependent manner. Modulation of HECT E3 ligase activity further altered ubiquitination dynamics and mHTT aggregation, suggesting that HECT E3 ligase-related pathways may contribute to proteostasis regulation in HD cells. Collectively, these findings identify USP28 as a proteostasis-associated deubiquitinase reduced in HD models and suggest that USP28 deficiency contributes to ubiquitin burden and mHTT aggregation. Changes in UBR5 expression further point to a potential involvement of HECT E3 ligase-linked ubiquitin regulation, although the direct mechanistic relationship between USP28 and UBR5 remains.
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