Autophagy pathway: Cellular and molecular mechanisms

Abstract

Macroautophagy/autophagy is an essential, conserved self-eating process that cells perform to allow degradation of intracellular components, including soluble proteins, aggregated proteins, organelles, macromolecular complexes, and foreign bodies. The process requires formation of a double-membrane structure containing the sequestered cytoplasmic material, the autophagosome, that ultimately fuses with the lysosome. This review will define this process and the cellular pathways required, from the formation of the double membrane to the fusion with lysosomes in molecular terms, and in particular highlight the recent progress in our understanding of this complex process.

Keywords: ATG proteins; RAB protein; SNARE; autophagic lysosome reformation; omegasome; phagophore.

Figure 1.

Autophagy pathway in mammalian cells. The molecular pathway comprised of the core autophagy proteins is illustrated with their associated autophagy membrane compartments. The 4 major steps in the autophagic pathway are shown in red. PtdIns3P, phosphatidylinositol 3-phosphate; PE, phosphatidylethanolamine.

Figure 2.

Intracellular organelles and membrane contacts facilitating autophagosome formation. (A) The major organelles required for the secretory pathway (ER, Golgi) and endocytosis (sorting endosome, recycling endosome) implicated in membrane contribution to phagophore formation. For simplicity not all ER-Golgi associated compartments (ERES, ERGIC, COP vesicles) are shown. Likewise not all endocytic-associated compartments (early endosome, late endosome, lysosome) are shown. (B) Membrane contact sites proposed or potentially implicated in phagophore expansion. The MAMs (mitochondria-associated membranes) are illustrated by contact of the phagophore with the mitochondria.

Figure 3.

Schematic illustration of autophagosome-lysosome fusion. The cytoskeleton components and related motor proteins, the tethering factors, core machinery SNAREs and phospholipids involved in the fusion process are indicated. The detailed molecular mechanisms of each factor are discussed in the text. MT, microtubule.

Figure 4.

The overview of the autophagic lysosome reformation (ALR) process. mTOR reactivation trigger ALR. Clathrin-mediated buds driving initiation, microtubules and the motor protein KIF5B mediating tube elongation, and DNM2 (dynamin 2)-mediated proto-lysosome scission couple with the function of multiple phospholipids.