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Ubiquitination occurs at synapses, yet its role remains unclear. Previous studies demonstrated that the RPM-1 ubiquitin ligase organizes presynaptic boutons at neuromuscular junctions in  C. elegans  motorneurons. Here we find that RPM-1 has a novel postsynaptic role in interneurons, where it regulates the trafficking of the AMPA-type glutamate receptor GLR-1 from synapses into endosomes. Mutations in  rpm-1  cause the aberrant accumulation of GLR-1 in neurites. Moreover,  rpm-1  mutations enhance the endosomal accumulation of GLR-1 observed in mutants for  lin-10 , a Mint2 ortholog that promotes GLR-1 recycling from Syntaxin-13 containing endosomes. As in motorneurons, RPM-1 negatively regulates the  pmk-3 /p38 MAPK pathway in interneurons by repressing the protein levels of the MAPKKK DLK-1. This regulation of PMK-3 signaling is critical for RPM-1 function with respect to GLR-1 trafficking, as  pmk-3  mutations suppress both  lin-10  and  rpm-1  mutations. Positive or negative changes in endocytosis mimic the effects of  rpm-1  or  pmk-3  mutations, respectively, on GLR-1 trafficking. Specifically, RAB-5(GDP), an inactive mutant of RAB-5 that reduces endocytosis, mimics the effect of  pmk-3  mutations when introduced into wild-type animals, and occludes the effect of  pmk-3  mutations when introduced into  pmk-3  mutants. By contrast, RAB-5(GTP), which increases endocytosis, suppresses the effect of  pmk-3  mutations, mimics the effect of  rpm-1  mutations, and occludes the effect of  rpm-1  mutations. Our findings indicate a novel specialized role for RPM-1 and PMK-3/p38 MAPK in regulating the endosomal trafficking of AMPARs at central synapses.

The Ubiquitin Ligase RPM-1 and the p38 MAPK PMK-3 Regulate AMPA Receptor Trafficking