UBQLN2 facilitates degradation of the retrotransposon protein PEG10 via UBE3A activity

Ubiquilins are a family of extrinsic ubiquitin receptors that are thought to facilitate protein degradation by shuttling proteins to the proteasome. However, the defining characteristics of Ubiquilin clients, and the steps of Ubiquilin-mediated degradation, have been elusive. Previously, we showed Ubiquilin 2 (UBQLN2) regulates the proteasomal degradation of PEG10, a unique virus-like protein which comes in two forms: a gag protein which is not regulated by UBQLN2, and a gag-pol protein which is dependent on UBQLN2. Here, we refine the model of Ubiquilin activity through the UBQLN2-mediated degradation of PEG10. UBQLN2 binding did not ensure degradation, and was independent of client ubiquitination, though ubiquitination of key lysine residues was necessary for gag-pol proteolysis. Ubiquitination was dependent on the E3 ubiquitin ligase UBE3A, which was surprisingly unable to regulate gag-pol in the absence of UBQLN2. Together, we have established a stepwise model of UBQLN2-mediated degradation that represents a new perspective on Ubiquilin function.