Regulation of autophagy by the Rab GTPase network

Abstract

Autophagy (macroautophagy) is a highly conserved intracellular and lysosome-dependent degradation process in which autophagic substrates are enclosed and degraded by a double-membrane vesicular structure in a continuous and dynamic vesicle transport process. The Rab protein is a small GTPase that belongs to the Ras-like GTPase superfamily and regulates the vesicle traffic process. Numerous Rab proteins have been shown to be involved in various stages of autophagy. Rab1, Rab5, Rab7, Rab9A, Rab11, Rab23, Rab32, and Rab33B participate in autophagosome formation, whereas Rab9 is required in non-canonical autophagy. Rab7, Rab8B, and Rab24 have a key role in autophagosome maturation. Rab8A and Rab25 are also involved in autophagy, but their role is unknown. Here, we summarize new findings regarding the involvement of Rabs in autophagy and provide insights regarding future research on the mechanisms of autophagy regulation.

Figure 1

Schematic model of autophagy. Autophagy is induced by various cellular stressors and is related to cellular homeostasis. Following the induction of autophagy, autophagic substrates are enclosed by an isolation membrane called a pre-autophagosome or phagophore that elongates to form an autophagosome with a double membrane (autophagosome formation), and eventually fuses with the lysosome to degrade the enclosed contents (autophagosome–lysosome fusion/autophagosome maturation and degradation)

Figure 2

Schematic diagram illustrating the regulation of autophagosome formation by Rab proteins. Following the induction of autophagy, autophagosome formation is regulated by Rab1 through the Atg9·Atg2-Atg18 complex, by Rab5 through the Vps34-Atg6/beclin1 class III PI3-kinase complex, by Rab33B through the Atg12 conjugation system, and by Rab7, Rab9A, Rab11, Rab23, and Rab32 via unknown molecular mechanisms. ER, endoplasmic reticulum

Figure 3

Schematic diagram illustrating the regulation of autophagosome–lysosome fusion by Rab proteins. Following autophagosome formation, autophagosome–lysosome fusion is regulated by Rab7 through microtubule plus/minus-end-directed transport, by Rab8B through its downstream effector TBK-1, and by Rab24 via unknown molecular mechanisms

Figure 4

Schematic diagram illustrating the regulation of autophagy by Rab proteins. The solid line shows the canonical autophagic process in which Rab1, Rab5, and Rab32 regulate autophagosome formation from the ER. Rab33B is involved in autophagosome formation from the GA, and autophagosome maturation into autolysosome is mediated by Rab7, Rab8B, and Rab24. The dotted line points to the fusion of MVB and RE with the autophagosome to form an amphisome that is regulated by Rab11. The dashed line indicates the formation and maturation of GcAVs; the homotypic fusion mediated by Rab7, Rab9A, and Rab23. Rab9A also participates in the fusion of GcAVs with lysosomes. ER, endoplasmic reticulum; GA, Golgi apparatus; GAS, Group A Streptococcus; GcAVs, GAS-containing autophagosome-like vacuoles; MVB, multivesicular bodies; PM, plasma membrane; RE, recycling endosome