Roles of Rab-GAPs in Regulating Autophagy

Autophagy maintains intracellular homeostasis by degrading unfavorable components and thereby supplying nutrients for renovation. During autophagy, double-membrane structures called isolation membranes form and elongate to surround the components to be degraded. The resulting closed spherical structures, called autophagosomes, then fuse with endosomes and lysosomes. Since autophagosomes are membranous structures, it is generally thought that a membrane supply from other organelles to isolation membranes is necessary to form autophagosomes. Membrane trafficking is a fundamental system by which organelles (or vesicles) are formed and by which proper communication between organelles is achieved, and a variety of proteins that are required for membrane trafficking have been identified and their roles determined in the past few decades. However, involvement of such proteins in autophagy was largely unknown for a long time. Recent studies have shown that Rab small GTPases, which are key regulators of membrane trafficking, play important roles in autophagy, and several Rab-GAPs (GTPase-activating proteins), negative regulators of Rabs, have been reported to be involved in autophagosome formation and maturation. In this chapter we provide an overview of the proposed functions of Rab-GAPs and discuss both their relation to the current model of autophagosome formation and maturation and the future Rab-GAP research.