We investigated how mitochondrial membrane proteins remain soluble in the 
cytosol until their delivery to mitochondria or degradation at the proteasome. 
We show that Ubiquilin family proteins bind transmembrane domains in the cytosol 
to prevent aggregation and temporarily allow opportunities for membrane 
targeting. Over time, Ubiquilins recruit an E3 ligase to ubiquitinate bound 
clients. The attached ubiquitin engages Ubiquilin's UBA domain, normally bound 
to an intramolecular UBL domain, and stabilizes the Ubiquilin-client complex. 
This conformational change precludes additional chances at membrane targeting 
for the client, while simultaneously freeing Ubiquilin's UBL domain for 
targeting to the proteasome. Loss of Ubiquilins by genetic ablation or 
sequestration in polyglutamine aggregates leads to accumulation of non-inserted 
mitochondrial membrane protein precursors. These findings define Ubiquilins as a 
family of chaperones for cytosolically exposed transmembrane domains and explain 
how they use ubiquitin to triage clients for degradation via coordinated intra- 
and intermolecular interactions.