CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono‐ubiquitination

Abstract

The development of neurological pathologies is linked to the accumulation of protein aggregates like alpha‐synuclein in Parkinson's disease and tau protein in Alzheimer's disease. Mono‐ or di‐ubiquitination of these molecules has been reported to stabilize aggregates and contribute to the disorders. STIP1 Homologous and U‐Box‐containing protein 1 (STUB1) is a multifunctional protein that maintains proteostasis and insulin signalling. In spinocerebellar ataxia 16 (SCAR16), an autosomal recessive neurodegenerative disease, mutations in and aggregation of STUB1 are reported. Despite the well‐accepted neuroprotective role of STUB1, very little is known of regulatory mechanisms that control the dynamics of STUB1 aggregate assembly. Here, we report that CARP2, a ubiquitin ligase, is a novel regulator of STUB1. CARP2 interacts and mono‐ubiquitinates STUB1. Furthermore, we found that CARP2 regulates STUB1 through its TPR motif, a domain that is also associated with HSP70. Modification of STUB1 by CARP2 leads to detergent‐insoluble aggregate formation. Importantly, pathogenic mutants of STUB1 are more prone than the wild‐type to CARP2‐mediated aggregate assembly. Hence our findings revealed CARPs (CARP1 & CARP2) as novel regulators of STUB1 and controlled its cytosolic versus aggregate dynamics.