Autophagy Pathway

Overview of Autophagy Pathways

Macroautophagy, hereafter referred to as autophagy, is a catabolic process by which cells degrade long-lived proteins, organelles, and certain types of bacteria via lysosomes. Briefly, the autophagy pathway entails the development of a phagophore that envelopes cytoplasmic components and forms a double-membrane autophagosome that subsequently fuses with a lysosome for the digestion of its contents. Of importance to a wide range of researchers, the autophagy pathway is thought to be protective against several diseases, including neurodegeneration, myopathy, liver disease, and diabetes. Additionally, autophagy appears to have a complex role in cancer, as it has been reported to both promote and inhibit cancer.

Autophagy is initiated by the generation of phosphatidylinositol 3-phosphate [PI(3)P]-rich regions of the endoplasmic reticulum (ER) that form phagophores, which are also referred to as omegasomes due to their shape. PI(3)P is generated by hVps34, the catalytic subunit of the Beclin 1 complex, and is required for the recruitment of downstream autophagy components, such as WIPI1/2 and DFCP1. The ULK1/2 kinase complex, including ULK1, ULK2, ATG13, and RB1CC1, is also required for autophagy initiation. It positively regulates the Beclin 1 complex indirectly by promoting its release from microtubules and possibly directly by phosphorylating Beclin 1 and stimulating hVps34 activity.

Phagophore elongation is thought to require mATG9 and the Ubiquitin-like protein, LC3. mATG9 is a transmembrane protein found mainly in the Golgi network that transiently interacts with phagophores in an ULK1-dependent manner during nutrient starvation. These transient interactions may contribute to membrane delivery during phagophore elongation. LC3 is converted to LC3-II, which is commonly used as an autophagy marker, in two steps. LC3 is first cleaved by ATG4B to form LC3-I. LC3-I is then translocated to phagophores via the Ubiquitin-activating (E1)-like enzyme ATG7 and the Ubiquitin-conjugating (E2)-like enzyme ATG3 where it is conjugated to phosphatidylethanolamine (PE) to form LC3-II. LC3-II formation is positively regulated by PI(3)P effector proteins, such as WIPI1/2, and the ATG16L-ATG5-ATG12 Ubiquitin-like complex. Interestingly, RB1CC1 may interact with ATG16L, which suggests that the ULK1/2 kinase complex might also function during phagophore elongation. LC3-II also binds substrates for autophagic degradation, referred to as cargo, via different adaptor proteins. For example, during mitochondrial autophagy, or mitophagy, LC3-II binds to mitochondria via the BNIP3L adaptor protein.

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