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The deubiquitinating enzyme USP 46 regulates AMPA receptor ubiquitination and trafficking
Author(s) -
Huo Yuda,
Khatri Natasha,
Hou Qingming,
Gilbert James,
Wang Guan,
Man HengYe
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13194
Subject(s) - deubiquitinating enzyme , ampa receptor , ubiquitin , microbiology and biotechnology , ubiquitin ligase , chemistry , synaptic plasticity , biology , nmda receptor , receptor , biochemistry , gene
Alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor ( AMPAR s) are the primary mediators for inter‐neuronal communication and play a crucial role in higher brain functions including learning and memory. Our previous work demonstrated that AMPAR s are subject to ubiquitination by the E3 ligase Nedd4, resulting in EPS 15‐mediated receptor internalization and Ubiquitin (Ub)–proteasome pathway ( UPP )‐dependent degradation. Protein ubiquitination is a highly dynamic and reversible process, achieved via the balance between ubiquitination and deubiquitination. However, deubiquitination of mammalian AMPAR s and the responsible deubiquitinating enzymes remain elusive. In this study, we identify USP 46 as the deubiquitinating enzyme for AMPAR s. We find that AMPAR s are subject to K63 type ubiquitination, and USP 46 is able to deubiquitinate AMPAR s in vivo and in vitro . In heterologous cells and neurons, expression of USP 46 results in a significant reduction in AMPAR ubiquitination, accompanied by a reduced rate in AMPAR degradation and an increase in surface AMPAR accumulation. By contrast, knockdown of USP 46 by RNA i leads to elevated AMPAR ubiquitination and a reduction in surface AMPAR s at synapses in neurons. Consistently, miniature excitatory postsynaptic currents recordings show reduced synaptic strength in neurons expressing USP 46‐selective RNA i. These results demonstrate USP 46‐mediated regulation of AMPAR ubiquitination and turnover, which may play an important role in synaptic plasticity and brain function.Protein ubiquitination is a highly dynamic and reversible process, achieved via the balance between ubiquitination and deubiquitination. The glutamatergic AMPARs, which mediate most of the excitatory synaptic transmission in the brain, are known to be subjected to Nedd4‐mediated ubiquitination; however, the deubiquitination process and the responsible deubiquitinating enzymes (DUBs) for mammalian AMPARs remain elusive. We find that AMPARs are subject to K63‐type ubiquitination, and identify USP46 as the DUB for AMPARs. USP46 deubiquitinates AMPARs in vitro and in vivo . Up‐ or down‐regulation of USP46 leads to changes in AMPAR ubiquitination, surface expression, and trafficking, as well as the strength of synaptic transmission. USP46‐mediated regulation of AMPAR ubiquitination and turnover may play an important role in synaptic plasticity and brain function.