A new V-ATPase regulatory mechanism mediated by the Rab interacting lysosomal protein (RILP)

Abstract

Progressive luminal acidification of intracellular compartments is important for their functions. Proton transport into the organelle's lumen is mediated by vacuolar ATPases (V-ATPases) large multi-subunit proton pumps organized into 2 domains, V0 and V1, working together as a rotary machine. The interaction of each subunit with specific partners plays a crucial role in controlling V-ATPase activity. Recently, we have shown that RILP, a Rab7 effector regulating late endocytic traffic and biogenesis of multivesicular bodies (MVBs), is a specific interactor of the V-ATPase subunit V1G1, a fundamental component of the peripheral stalk for correct V-ATPase assembly. RILP controls V1G1 stability and localization affecting V-ATPase assembly and function at the level of endosomes and lysosomes. The discovery of this new regulatory mechanism for V-ATPase opens new scenario to the comprehension of organelle's pH regulation and reveals a key role of RILP in controlling different aspects of endosome to lysosome transport.

Keywords: Endocytosis; Membrane traffic; RILP; Rab proteins; Rab7; Ubiquitin; V-ATPase; V1G1; atp6v1g1.

Figure 1.

A model for the role of RILP in the recruitment of the V1 domain onto late endosome and lysosomes. The pH along the endocytic pathway gradually decreases from endosomes to lysosomes. The recruitment of RILP on endosomes and lysosomes, mediated by GTP-bound Rab7, promotes the subsequent recruitment of the V1 domain inducing reassembly of the V-ATPase, through the interaction of RILP with the V1G1 subunit. Depletion of RILP prevents the recruitment of V1G1 on late endosomal and lysosomal membranes promoting mislocalization of the V1G1 subunit (and possibly of the V1 domain) on Golgi membranes and affecting organelle's pH.