Involvement of members of the Rab family and related small GTPases in autophagosome formation and maturation

Abstract

Macroautophagy, the process by which cytosolic components and organelles are engulfed and degraded by a double-membrane structure, could be viewed as a specialized, multistep membrane transport process. As such, it intersects with the exocytic and endocytic membrane trafficking pathways. A number of Rab GTPases which regulate secretory and endocytic membrane traffic have been shown to play either critical or accessory roles in autophagy. The biogenesis of the pre-autophagosomal isolation membrane (or phagophore) is dependent on the functionality of Rab1. A non-canonical, Atg5/Atg7-independent mode of autophagosome generation from the trans-Golgi or endosome requires Rab9. Other Rabs, such as Rab5, Rab24, Rab33, and Rab7 have all been shown to be required, or involved at various stages of autophagosomal genesis and maturation. Another small GTPase, RalB, was very recently demonstrated to induce isolation membrane formation and maturation via its engagement of the exocyst complex, a known Rab effector. We summarize here what is now known about the involvement of Rabs in autophagy, and discuss plausible mechanisms with future perspectives.

Fig. 1

Schematic diagram illustrating the membrane compartments in the exocytic and endoscytic machinery that is connected to autophagosome formation and maturation. As depicted, the omegasome (Ω) is associated with the ER, but IM membranes could have a source in ER, Golgi, TGN, and the mitochondria. Also shown are the Rabs with a demonstrated involvement in autophagy, as well as RalB. The blue arrow indicates the generation of a double membrane enclosed immature autophagosome, or autophagic vesicle, from the ER. Blue dotted arrows point to potential endocytic compartments this vesicle could fuse with during its subsequent maturation. Black arrows indicate membrane traffic flow between the endocytic compartments. PM plasma membrane, MVB multivesicular bodies, LE late endosome, TGN trans-Golgi network, GA Golgi apparatus