RILP: a new way to regulate V-ATPase Free

Vacuolar (V-)ATPases are responsible for proton transport across the plasma membrane; they consist of a V0 transmembrane domain that is involved in proton translocation and a peripheral V1 domain on the cytoplasmic site of the membrane that is responsible for ATP hydrolysis. Owing to their fundamental role in regulating the pH of intracellular organelles and the extracellular milieu, V-ATPases have been implicated in a number of diseases, including renal tubule acidosis, diabetes and cancer. Further insights into the regulation of V-ATPase activity, such as the discovery of new interaction partners will, thus, be valuable. Rab-interacting lysosomal protein (RILP) is an effector of the small GTPase Rab7; it is recruited to endosomal membranes through GTP-bound Rab7, and together they control trafficking to late endosomes and lysosomes in the endocytic route. In this work (p. 2697), Cecilia Bucci and colleagues use a yeast two-hybrid system to identify new RILP-interaction factors and identify the V1G1 (officially known as ATP6V1G1) subunit of V-ATPase. The authors then perform co-immunoprecipitation experiments to confirm the physiological relevance of the interaction between RILP and V1G1, and also show that this interaction is a direct one. Indeed, they demonstrate that RILP is not only important in recruiting V1G1 to the endosomal membrane but that it also fine-tunes the levels of V1G1 by inducing its ubiquitylation and, thus, proteosomal degradation, which, in turn, affects the activity of V-ATPase. The interaction of V1G1 with RILP, thus, represents a new molecular mechanism for the regulation of V-ATPase that may be exploited to develop new therapeutic strategies to treat conditions that are caused by aberrant V-ATPase activity.