HTT (huntingtin) and RAB7 co-migrate retrogradely on a signaling LAMP1-containing late endosome during axonal injury

HTT (huntingtin) is a 350-kDa protein of unknown function. While HTT moves bidirectionally within axons and HTT loss/reduction causes axonal transport defects, the identity of cargo-containing vesicles that HTT helps move remain elusive. Previously, we found an axonal retrogradely moving HTT-Rab7 vesicle complex; however, its biological relevance is unclear. Using Drosophila genetics, in vivo microscopy, membrane isolation and pharmacological inhibition, here we identified that adaptors Hip1 and Rilpl aid the retrograde motility of LAMP1-containing HTT-Rab7 late endosomes, not autophagosomes. Reduction of Syx17 and chloroquine- or bafilomycin A(1)-mediated pharmacological inhibition, but not reduction of Atg5, disrupted the in vivo motility of these vesicles. Further, because HTT-Rab7 vesicles colocalized with long-distance signaling components (BMP signaling: tkv-wit, injury: wnd) and move in a retrograde direction after Drosophila nerve crush, we propose that these vesicles likely traffic damage signals following axonal injury. Together, our findings support a previously unknown role for HTT in the retrograde movement of a Rab7-LAMP1-containing signaling late endosome.