C9orf72 protein quality control by UBR5-mediated heterotypic ubiquitin chains

ABSTRACT: Hexanucleotide repeat expansions within C9orf72 are a frequent cause of amyotrophic lateral sclerosis and frontotemporal dementia. Haploinsufficiency leading to reduced C9orf72 protein contributes to disease pathogenesis. C9orf72 binds SMCR8 to form a robust complex that regulates small GTPases, lysosomal integrity and autophagy. In contrast to this functional understanding, we know far less about assembly and turnover of the C9orf72-SMCR8 complex. Loss of either subunit causes the concurrent ablation of the respective partner. However, the molecular mechanism underlying this interdependence remains elusive. Here, we identify C9orf72 as substrate of branched ubiquitin chain-dependent protein quality control. We find that SMCR8 prevents C9orf72 from rapid degradation by the proteasome. Mass

SUBMITTER: Julia Jülg 

PROVIDER: S-SCDT-10_15252-EMBR_202255895 | biostudies-other |

REPOSITORIES: biostudies-other