UBQLN2 is necessary for UBE3A-mediated proteasomal degradation of the domesticated retroelement PEG10. | CU Experts

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 further investigation of the UBQLN2-mediated degradation of PEG10. Gag-pol and gag proteins undergo distinct degradation processes; while both forms bind to UBQLN2 independent of their ubiquitination status, only gag-pol protein is degraded in a UBQLN2, ubiquitin, and proteasome-dependent fashion. Cellular gag-pol is ubiquitinated, and mutation of key lysine residues in the pol region rendered gag-pol insensitive to UBQLN2. Degradation of gag-pol was also dependent on the E3 ubiquitin ligase UBE3A, which requires UBQLN2 to regulate gag-pol levels. Together, these data clarify our understanding of UBQLN2-mediated degradation and highlight the importance of UBE3A in regulating PEG10.

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