Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy

Although protein inclusions associated with neurodegenerative diseases are typically enriched with ubiquitin, it is currently unclear whether the topology of ubiquitin linkage plays a role in their biogenesis. In an attempt to clarify this, our recent work identified K63-linked polyubiquitin as a key regulator of inclusion dynamics. We found in the setting of ectopic overexpression of different ubiquitin species in cultured cells that K63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions linked to several major neurodegenerative diseases. Further supporting this, we report here a similar phenomenon in cells co-expressing Ubc13 and Uev1a but not those expressing UbcH7 or UbcH8. Notably, Ubc13 in association with Uev1a is known to promote K63-linked ubiquitination. In exploring how K63-linked ubiquitination could promote the clearance of inclusions by autophagy, we also found in our current study that K63-linked polyubiquitin interacts with p62, a ubiquitin-binding ...