Protein quality control machinery supports primary ciliogenesis by eliminating GDP-bound Rab8-family GTPases

The small GTPase Rab8 plays a vital role in the vesicular trafficking of cargo proteins from the trans-Golgi network to target membranes. Upon reaching its target destination, Rab8 is released from the vesicular membrane into the cytoplasm via guanosine triphosphate (GTP) hydrolysis. The fate of GDP-bound Rab8 released from the destination membranes, however, has not been investigated adequately. In this study, we found that GDP-bound Rab8 subfamily proteins are targeted for immediate degradation, and the pre-emptive quality control machinery is responsible for eliminating these proteins in a nucleotide-specific manner. We provide evidence that components of this quality control machinery have a critical role in vesicular trafficking events, including the formation of primary cilia, a process regulated by the Rab8 subfamily. These results suggest that the protein degradation machinery plays a critical role in the integrity of membrane trafficking by limiting the excessive accumulation of GDP-bound Rab8 subfamily proteins. [Display omitted] •GDP-bound Rab8 subfamily proteins are polyubiquitinated for degradation•UBQLN4 is required for Rab8a degradation in a nucleotide-specific manner•RNF126 plays a critical role in the degradation of GDP-bound Rab8a•The protein degradation machinery is necessary for primary cilium formation Molecular biology; Cell biology