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bioRxiv · 10.1101/515999

Nedd4 E3 ligase and beta-arrestins regulate ubiquitination, trafficking, and stability of the mGlu7 receptor

Suh, Y. H.·Lee, S.·Park, S.·Lee, H.·Han, S.·Song, J.-m.·Han, D.
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Abstract

The metabotropic glutamate receptor 7 (mGlu7) is a class C G protein-coupled receptor (GPCR) that modulates excitatory neurotransmitter release at the presynaptic active zone. Although post-translational modification of cellular proteins with ubiquitin is a key molecular mechanism governing protein degradation and function, mGlu7 ubiquitination and its functional consequences have not been elucidated yet. Here, we report that Nedd4 ubiquitin E3 ligase and {beta}-arrestins regulate ubiquitination of mGlu7 in heterologous cells and neurons. Upon agonist-stimulation, {beta}-arrestins recruit Nedd4 to mGlu7 and facilitate Nedd4-mediated ubiquitination of mGlu7. Nedd4 and {beta}-arrestins regulate constitutive and agonist-induced endocytosis of mGlu7 and are required for mGlu7-dependent MAPK signaling in neurons. In addition, Nedd4-mediated ubiquitination results in the degradation of mGlu7 by both the lysosomal and proteasomal degradation pathways. These findings provide a model in which Nedd4 and {beta}-arrestin act together as a complex to regulate mGlu7 surface expression and function at the presynaptic terminals.

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Suh, Y. H., Lee, S., Park, S., Lee, H., Han, S., Song, J.-m., Han, D.. 2019-01-09. Nedd4 E3 ligase and beta-arrestins regulate ubiquitination, trafficking, and stability of the mGlu7 receptor. https://doi.org/10.1101/515999

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