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UNC-104/KIF1A is a Kinesin-3 motor that transports synaptic vesicles from the cell body towards the synapse by binding to PI(4,5)P 2  through its PH domain. The fate of the motor upon reaching the synapse is not known. We found that wild-type UNC-104 is degraded at synaptic regions through the ubiquitin pathway and is not retrogradely transported back to the cell body. As a possible means to regulate the motor, we tested the effect of cargo binding on UNC-104 levels. The  unc-104(e1265)  allele carries a point mutation (D1497N) in the PI(4,5)P 2  binding pocket of the PH domain, resulting in greatly reduced preferential binding to PI(4,5)P 2   in vitro  and presence of very few motors on pre-synaptic vesicles  in vivo .  unc-104(e1265)  animals have poor locomotion irrespective of  in vivo  PI(4,5)P 2  levels due to reduced anterograde transport. Moreover, they show highly reduced levels of UNC-104  in vivo . To confirm that loss of cargo binding specificity reduces motor levels, we isolated two intragenic suppressors with compensatory mutations within the PH domain. These show partial restoration of  in vitro  preferential PI(4,5)P 2  binding and presence of more motors on pre-synaptic vesicles  in vivo . These animals show improved locomotion dependent on  in vivo  PI(4,5)P 2  levels, increased anterograde transport, and partial restoration of UNC-104 protein levels  in vivo . For further proof, we mutated a conserved residue in one suppressor background. The PH domain in this triple mutant lacked  in vitro  PI(4,5)P 2  binding specificity, and the animals again showed locomotory defects and reduced motor levels. All allelic variants show increased UNC-104 levels upon blocking the ubiquitin pathway. These data show that inability to bind cargo can target motors for degradation. In view of the observed degradation of the motor in synaptic regions, this further suggests that UNC-104 may get degraded at synapses upon release of cargo.

The Caenorhabditis elegans Kinesin-3 Motor UNC-104/KIF1A Is Degraded upon Loss of Specific Binding to Cargo