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The role of ubiquilin in AMPA receptor ubiquitination and proteasomal degradationGuo, Ouyang 21 July 2016 (has links)
Ubiquilin (UBQLN) is a member of type2 ubiquitin-like (UBL) protein family characterized by an UBL domain at the N-terminus and an ubiquitin associated (UBA) domain at the C-terminus. This protein has been shown to play an important role in the regulation of the levels, aggregation and degradation of various neurodegenerative disease-associated proteins. However, the specific functions and mechanisms of UBQLN regulation still remain to be elucidated. In this study, we investigate the effect of UBQLN expression on α-Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR) degradation and the underlying molecular mechanisms. We show that UBQLN overexpression decreases AMPAR levels in neurons and also reduces GluA1 expression in HEK 293T cells. Moreover, our results indicate that UBQLN can form a complex with GluA1, and this interaction is related to the ubiquitination of AMPARs. In addition, we find a higher expression of UBQLN2 in Alzheimer’s disease (AD) patient brains, which might be a potential pathological mechanism of GluA1 reduction in AD. Given the crucial effect of UBQLN in AMPAR regulation, UBQLN may play an important role in synaptic transmission, brain functions as well as neurodegenerative diseases. / 2018-07-21T00:00:00Z
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Ubiquilin-2 associates with ubiquitinated AMPA receptors for proteasomal degradationSreeram, Aparna 09 August 2019 (has links)
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
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