Abstract
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.
Highlights
Synapses are the sites of cellular communication between presynaptic neurons and their postsynaptic partners
Double mutants using molecular null alleles for lin-10 and rpm-1 have significantly larger accretions of GLR-1 than either single mutant alone (Fig. 1D,I), and have reduced numbers of small GLR-1 puncta compared to wild type (Fig. 1J), suggesting that these two genes might act in separate pathways to regulate GLR-1 trafficking
We identified a novel role for RPM-1 and PMK-3 as regulators of AMPAtype GluRs (AMPARs) endocytosis
Summary
Synapses are the sites of cellular communication between presynaptic neurons and their postsynaptic partners. Presynaptic terminals contain multiple synaptic vesicles, which release neurotransmitter [1]. Receptors on the postsynaptic side of the synapse receive the neurotransmitter signals from the presynaptic cell. The formation of presynaptic terminals and postsynaptic specializations is coordinated, but requires distinct sets of proteins. Numerous regulators of presynaptic terminals at neuromuscular junctions (NMJs) have been identified. A conserved family of proteins, the PHR proteins (including vertebrate Phr and Pam, Drosophila Highwire, and C. elegans RPM-1), regulates the assembly of presynaptic components at NMJs [3,4,5,6,7,8]. PHR proteins contain multiple domains, including several RCC1 repeats, two repeats termed PHR domains, and a RING H2 domain. PHR proteins have both E3 ubiquitin ligase activity and guanine nucleotide exchange factor (GEF) activity, and can bind to Myc, adenylate cyclase, tuberin, the co-SMAD Medea, and dual leucine zipper kinases (DLKs) known to regulate the p38 MAP Kinase (MAPK) pathway [3,9,10,11,12,13,14]
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