The WD40-Repeat Protein WDR-20 and the Deubiquitinating Enzyme USP-46 Promote Cell Surface Levels of Glutamate Receptors
Year: 2021
Type: article
Abstract: Reversible modification of AMPA receptors (AMPARs) with ubiquitin regulates receptor levels at synapses and controls synaptic strength. The conserved deubiquitinating enzyme (DUB) ubiquitin-specific protease-46 (USP-46) removes ubiquitin from AMPARs and protects them from degradation in bothCaenorhabditis elegansand mammals. Although DUBs are critical for diverse physiological processes, the mechanisms that regulate DUBs, especially in the nervous system, are not well understood. We and others previously showed that the WD40-repeat proteins WDR-48 and WDR-20 bind to and stimulate the catalytic activity of USP-46. Here, we identify an activity-dependent mechanism that regulates WDR-20 expression and show that WDR-20 works together with USP-46 and WDR-48 to promote surface levels of theC. elegansAMPAR GLR-1.usp-46,wdr-48, andwdr-20loss-of-function mutants exhibit reduced levels of GLR-1 at the neuronal surface and corresponding defects in GLR-1-mediated behavior. Increased expression of WDR-20, but not WDR-48, is sufficient to increase GLR-1 surface levels in anusp-46-dependent manner. Loss ofusp-46,wdr-48, andwdr-20function reduces the rate of local GLR-1 insertion in neurites, whereas overexpression ofwdr-20is sufficient to increase the rate of GLR-1 insertion. Genetic manipulations that chronically reduce or increase glutamate signaling result in reciprocal alterations inwdr-20transcription and homeostatic compensatory changes in surface GLR-1 levels that are dependent onwdr-20. This study identifieswdr-20as a novel activity-regulated gene that couples chronic changes in synaptic activity with increased local insertion and surface levels of GLR-1 via the DUB USP-46. SIGNIFICANCE STATEMENTDeubiquitinating enzymes (DUBs) are critical regulators of synapse development and function; however, the regulatory mechanisms that control their various physiological functions are not well understood. This study identifies a novel role for the DUB ubiquitin-specific protease-46 (USP-46) and its associated regulatory protein WD40-repeat protein-20 (WDR-20) in regulating local insertion of glutamate receptors into the neuronal cell surface. This work also identifies WDR-20 as an activity-regulated gene that couples chronic changes in synaptic activity with homeostatic compensatory increases in surface levels of GLR-1 via USP-46. Given that 35% of USP family DUBs associate with WDR proteins, understanding the mechanisms by which WDR proteins regulate USP-46 could have implications for a large number of DUBs in other cell types.
Source: Journal of Neuroscience
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Awards: Regulation of glutamate receptors at synapses by WD40 repeat proteins and the deubiquitinating enzyme USP-46 in C. elegans, G2111793168, An optogenetic behavioral screen for conserved genes that regulate glutamatergic synapses, Synapse Neurobiology Training Program, A Compensatory Muscle-to-Neuron Feedback Pathway in C. Elegans, G3331747239, G4627842680, G5285256507, Training in Education and Critical Research Skills, G7993984576, G865804637, G9000028377, Caenorhabditis Genetics Center
OpenAlex ID: W3131315872