A catalytic independent function of the deubiquitinating enzyme USP14 regulates hippocampal synaptic short-term plasticity and vesicle number.
The ubiquitin proteasome system is required for the rapid and precise control of protein abundance that is essential for synaptic function. USP14 is a proteasome-bound deubiquitinating enzyme that recycles ubiquitin and regulates synaptic short-term synaptic plasticity. We previously reported that loss of USP14 in ax(J) mice causes a deficit in paired pulse facilitation (PPF) at hippocampal synapses. Here we report that USP14 regulates synaptic function through a novel, deubiquitination-independent mechanism. Although PPF is usually inversely related to release probability, USP14 deficiency impairs PPF without altering basal release probability. Instead, the loss of USP14 causes a large reduction in the number of synaptic vesicles. Over-expression of a catalytically inactive form of USP14 rescues the PPF deficit and restores synaptic vesicle number, indicating that USP14 regulates presynaptic structure and function independently of its role in deubiquitination. Finally, the PPF deficit caused by loss of USP14 can be rescued by pharmacological inhibition of proteasome activity, suggesting that inappropriate protein degradation underlies the PPF impairment. Overall, we demonstrate a novel, deubiquitination-independent function for USP14 in influencing synaptic architecture and plasticity.
1825 University Blvd, SHEL 902, Birmingham, AL 35210, USA.  dobrunz@uab.edu; S. M. Wilson: 1825 University Blvd, SHEL 914, Birmingham, AL 35294, USA. Email: wilson@nrc.uab.edu.
Brandon J
BJ
Walters
Jada J
JJ
Hallengren
Christopher S
CS
Theile
Hidde L
HL
Ploegh
Scott M
SM
Wilson
Lynn E
LE
Dobrunz
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009473:Neuronal Plasticity; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C469268:Usp14 protein, mouse; D043222:Ubiquitin Thiolesterase