Interaction between small GTPase Rab7 and PI3KC3 links autophagy and endocytosis: A new Rab7 effector protein sheds light on membrane trafficking pathways

Abstract

Endocytosis and autophagy are both membrane trafficking pathways vital for cell survival. Endocytosis, the primary means by which cells internalize material such as cell-surface receptors and their protein ligands, is essential for proper cell growth and communication. Autophagy is a catabolic process that degrades cargo ranging from organelles to protein aggregates to bacteria, and it is important for maintaining cellular homeostasis. Defects in both endosome and autophagosome maturation lead to an array of human diseases, including cancer; however, the molecular mechanisms underlying endosome and autophagosome maturation are not well characterized. In the case of endocytosis, small GTPases, key players in membrane organization, are required for endosome maturation. Specifically, activation of the small GTPase Rab7 is required for the initiation of the early-to-late endosome transition, although how this is regulated is largely unknown. Now recent findings from our laboratory show that Rubicon, a component of the PI3KC3 complex, inhibits endosome maturation by preventing activation of Rab7. Not only do our results clarify the molecular link between PI3KC3 and Rab7 function in endosome maturation, they lead us to propose new models for PI3KC3 involvement in membrane trafficking, particularly at the convergence between the endosome and autophagosome pathways.

Figure 1

A cartoon model of UVRAG-Rubicon in autophagosome and endosome maturation. UVRAG (the General) acts as a strong activator for both PI3KC3 and HOPS, but it is only active if it escapes the sequestration of Rubicon (by crossing the Rubicon river). Rab7 (the boat) allows UVRAG to sail through the Rubicon by competing for its binding with Rubicon, leading to PI3KC3 and HOPS activation and lysosomal degradation.