KIF13A mediates the activity-dependent transport of ESCRT-0 proteins in axons

Turnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy, functional synapses in neurons. Our previous work showed that the degradation of SV proteins is mediated by the endosomal sorting complex required for transport (ESCRT) pathway in an activity-dependent manner. Here, we characterize the axonal transport dynamics of ESCRT-0 proteins Hrs and STAM1, the first components of the ESCRT pathway critical for initiating SV protein degradation. Hrs- and STAM1-positive transport vesicles exhibit increased anterograde and bidirectional motility in response to neuronal firing, and frequent colocalization with SV pools. These ESCRT-0 vesicles are a subset of Rab5-positive structures in axons, likely representing pro-degradative early endosomes. Further, we identify kinesin motor protein KIF13A as essential for the activity-dependent transport of ESCRT-0 vesicles as well as the degradation of SV membrane proteins. Together, these data demonstrate a novel KIF13A-dependent mechanism for mobilizing axonal transport of ESCRT machinery to facilitate the degradation of SV proteins.