A Novel Ubiquitin E2 Variant Protein Acts in Axon Termination and Synaptogenesis in C.elegans

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In C.elegans, loss of function of the PHR protein RPM-1 (Regulator of Presynaptic Morphology) results in fewer synapses to form, disorganization in presynaptic terminal architecture and axon overextension in some neurons. Such defects are suppressed by inactivation of the DLK-1 pathway, which activates a p38 MAP kinase to regulate mRNA stability of a bZip domain protein. By characterizing additional genetic suppressors of rpm-1, we present here a new member of this DLK-1 pathway, uev-3, which is a E2 ubiquitin conjugating enzyme variant. uev-3 acts cell autonomously in neurons, despite its ubiquitous expression. Our genetic epistasis analysis shows that uev-3 acts downstream of MKK-4, the MAPKK, but upstream of the MAPKAPK MAK-2. We found UEV-3 physically interacts with MAPK PMK-3. The UEV domain is necessary for the function of UEV-3. We postulate that UEV-3 may limit the substrates accessible to PMK-3 to provide additional specificity in the DLK-1 pathway.