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bioRxiv · 10.1101/2021.08.19.457026

The active zone protein Clarinet regulates ATG-9 trafficking at synapses and presynaptic autophagy

Xuan, Z.·Yang, S.·Hill, S. E.·Clark, B.·Manning, L.·Colon-Ramos, D.
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Abstract

In neurons, autophagy is temporally and spatially regulated to occur near presynaptic sites. How trafficking of autophagy proteins is regulated to support synaptic autophagy is not well understood. From forward genetic screens, we identify a role for the long isoform of the active zone protein Clarinet (CLA-1L) in regulating trafficking of autophagy protein ATG-9 at synapses, and presynaptic autophagy. ATG-9 is a transmembrane protein that undergoes activity-dependent exo-endocytosis at synapses, and mutations in CLA-1L result in abnormal accumulation of ATG-9 into clathrin-rich endocytic intermediates. CLA-1L extends from the active zone to the periactive zone, and genetically interacts with periactive zone proteins required for clathrin-dependent endocytosis. We find that CLA-1L is specifically required for sorting of ATG-9 at synapses, likely via endosome-mediated endocytosis, and for activity-dependent presynaptic autophagy. Our findings provide mechanistic insights into how active zone proteins regulate key steps of ATG-9 exo-endocytosis, a process that could couple the activity state of the neuron and autophagy. HighlightsO_LI* The long isoform of the active zone protein Clarinet (CLA-1L) regulates ATG-9 trafficking at synapses C_LIO_LI* CLA-1L extends from the active zone to the periactive zone and cooperates with the periactive zone endocytic proteins EHS-1/EPS15 and ITSN-1/ intersectin 1 in ATG-9 trafficking during exo-endocytosis C_LIO_LI* Mutations in CLA-1L, or in clathrin-associated adaptor molecules, result in abnormal accumulation of ATG-9 into clathrin-rich endocytic intermediates C_LIO_LI* CLA-1L mutants which affect ATG-9 trafficking are also defective in activity-dependent presynaptic autophagy C_LI

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Xuan, Z., Yang, S., Hill, S. E., Clark, B., Manning, L., Colon-Ramos, D.. 2021-08-19. The active zone protein Clarinet regulates ATG-9 trafficking at synapses and presynaptic autophagy. https://doi.org/10.1101/2021.08.19.457026

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