Abstract
Autophagy is an intracellular catabolic process prominent in starvation, aging and disease. Neuronal autophagy is particularly important, as it affects the development and function of the nervous system, and is heavily implicated in neurodegenerative disease. Nonetheless, how autophagy is regulated in neurons remains poorly understood. Using an unbiased proteomics approach, we demonstrate that the primary initiator of autophagy, the UNC-51/ULK kinase, is negatively regulated by the ubiquitin ligase RPM-1. RPM-1 ubiquitin ligase activity restricts UNC-51 and autophagosome formation within specific axonal compartments, and exerts effects broadly across the nervous system. By restraining UNC-51 activity, RPM-1 inhibits autophagosome formation to affect axon termination, synapse maintenance and behavioral habituation. These results demonstrate how UNC-51 and autophagy are regulated subcellularly in axons, and unveils a mechanism for restricting initiation of autophagy across the nervous system. Our findings have important implications beyond nervous system development, given growing links between altered autophagy regulation and neurodegenerative diseases.
Highlights
Autophagy is an intracellular catabolic process prominent in starvation, aging and disease
Understanding the underpinnings of how autophagy is regulated in the nervous system is of the utmost importance
We show that the ubiquitin ligase RPM-1 restricts the autophagy initiating kinase UNC-51/UNC-51-like kinase (ULK) in neurons to promote axon termination and synapse maintenance (Fig. 9)
Summary
Autophagy is an intracellular catabolic process prominent in starvation, aging and disease. By restraining UNC-51 activity, RPM-1 inhibits autophagosome formation to affect axon termination, synapse maintenance and behavioral habituation These results demonstrate how UNC-51 and autophagy are regulated subcellularly in axons, and unveils a mechanism for restricting initiation of autophagy across the nervous system. To provide a functional context for these observations, we show that inhibition of ULK and autophagy by RPM-1 is required for axon termination, synapse maintenance, and behavioral habituation These findings reveal how initiation of autophagy is spatially restricted in subcellular compartments during neuron development, and indicate that ubiquitin ligase activity inhibits ULK and autophagy in the nervous system. These findings could have important implications beyond neuronal development as RPM-1, and other. Inhibitors of autophagy initiation like RPM-1 could be valuable targets for increasing autophagy to treat disease
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