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

The components of ubiquitin (Ub)‐proteasome system, such as Ub, Ub adaptors, or proteasome subunits, are commonly accumulated with the aggregated proteins in inclusions, but how protein aggregates sequester Ub‐related proteins remains elusive. Using N‐terminal huntingtin (Htt‐N552) and ataxin (Atx)‐3 as model proteins, we investigated the molecular mechanism underlying sequestration of Ub adaptors by polyQ‐expanded proteins. We found that polyQ‐expanded Htt‐N552 and Atx‐3 sequester endogenous Ub adaptors, human RAD23 homolog B (hHR23B) and ubiquilin (UBQLN)‐2, into inclusions. This sequestration effect is dependent on the UBA domains of Ub adaptors and the conjugated Ub of the aggregated proteins. Moreover, polyQ‐expanded Htt‐N552 and Atx‐3 reduce the protein level of xeroderma pigmentosum group C (XPC) by sequestration of hHR23B, suggesting that this process may cut down the available quantity of hHR23B and thus affect its normal function in stabilizing XPC. Our findings demonstrate that polyQ‐expanded proteins sequester Ub adaptors or other Ub‐related proteins into aggregates or inclusions through ubiquitination of the pathogenic proteins. This study may also provide a common mechanism for the formation of Ub‐positive inclusions in cells.—Yang, H., Yue, H.‐W., He, W.‐T., Hong, J.‐Y., Jiang, L.‐L., Hu, H.‐Y. PolyQ‐expanded huntingtin and ataxin‐3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin. FASEB J. 32, 2923–2933 (2018). www.fasebj.org