JIP4 and RILPL1 utilize opposing motor force to dynamically regulate lysosomal tubulation.

Abstract

Lysosomes are dynamic organelles that remodel their membrane in response to stimuli. We previously uncovered a process we term LYsosomal Tubulation/sorting driven by LRRK2 (LYTL), wherein damaged lysosomes generate tubules sorted into vesicles. LYTL is orchestrated by the Parkinson's disease kinase LRRK2 that recruits the motor adaptor protein and RHD family member JIP4 to lysosomes. JIP4 enhances LYTL tubule extension toward the plus-end of microtubules. To identify new players involved in LYTL, we mapped the lysosomal proteome after LRRK2 kinase inhibition. We found that RILPL1 is recruited to dysfunctional lysosomes in an LRRK2 kinase activity-dependent manner, facilitated by pRAB proteins. Unlike JIP4, RILPL1 induces retraction of LYTL tubules by binding to p150Glued, thereby moving lysosomal tubules toward the minus-end of microtubules. Our findings emphasize the dynamic regulation of LYTL tubules by two distinct RHD proteins and pRAB effectors, acting as opposing motor adaptor proteins. These opposing forces create a metastable lysosomal membrane deformation, enabling dynamic tubulation events.