Ubiquilin (UBQL) is a member of type 2 ubiquitin-like (UBL) protein family. They structurally contain an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated (UBA) domain. Ubiquilin 2 (UBQL2) physically associates with poly ubiquitinated proteins and delivers them to the proteasome for degradation. This protein has been shown to play an important role in the regulation of aggregation and degradation of various neurodegenerative disease-associated proteins. In this study, we looked into the role of the ubiquilin-2 proteins in the AMPA receptor ubiquitination and proteasomal degradation pathway. Our results indicate that UBQL2 overexpression decreases AMPAR levels in neurons and also reduces GluA1 expression in HEK 293T cells. Moreover, by co-immunoprecipitation we found that UBQL2 interacts with ubiquitinated AMPARs. We, therefore propose that UBQL2 brings AMPARs to the proteasome for degradation. Consistent with this notion, expression of UBQL2 P497H, a mutant form incapable of interaction with proteasome, causes accumulation of AMPA receptors. These results indicate a role for UBQL2 in associating with and directing ubiquitinated AMPA receptors to the proteasome for degradation. / 2020-08-09T00:00:00Z