Fig. 1

A schematic illustration of three types of autophagy and key regulatory molecules of autophagy flux inside cell. a: Three types of autophagy may occur in cell; microautophagy, chaperone-mediated autophagy, and macroautophagy [19, 20]. Microautophagy is the process during which damaged biomolecules are directly sorted into lysosomes. In chaperone-mediated autophagy, HSC70 identifies proteins containing specific motifs (KFERQ) and sorts them into lysosome through interaction with LAMP2A molecules placed on lysosome membrane. Macroautophagy mediates the lysosomal degradation of damaged proteins and organelles through 4 steps including initiation, nucleation, maturation, and finally fusion the autophagosome with lysosomes. Several proteins such as ULK, ATG13, FIP200, ARG101, Beclin-1, ATG14L, ATG5, ATG12, ATG16L, LC3, and PE, in different steps, mediate the formation of autophagosome [19, 20]. b: Once autophagy is induced, cytoplasmic dysfunctional molecules are encapsulated via double membranes, beginning from the formation of the phagophore to the autophagosomes, which consequently fuse with lysosomes and then their cargo is degraded [24]. Several ATG-associated assemblies including ULK-1 initiation complex, the PI3K III nucleation complex, the ATG12 conjugated complex, and the LC3 conjugation complex are involved in autophagy flux, which finally direct cytoplasmic dysfunctional molecules into lysosomes [24]. Stress condition such as starvation, energy depletion, reactive oxygen species (ROS), and hypoxia inhibit mTOR and growth factors act as activators of mTOR. Inhibition of mTOR activates the ULK-1 initiation complex which, in turn, mediates initiation of autophagy flux. In this scenario, AGT9 and the PI3K III nucleation complex collaborate with the ULK-1 initiation complex and progress initiation step of autophagy [24]. These complexes are supported by the ATG12 conjugation complex and the LC3 conjugation complex for completing initiation step and formation of phagophore in nucleation step. In order to formation of the ATG12 conjugation complex, ATG12 attaches to ATG5 and ATG16L1, and then the PI3P-binding complex (WIPIs and DFCP1) joins them to form the ATG12 conjugation complex. Formation of the ATG12 conjugation complex then facilitates connection of LC3 conjugation complex to newly formed phagophore in nucleation step, at this moment, ATG4 catalyzes the formation of LC3-I from LC3. Next, conjugation of PE with LC3-I, in presence of ATG7 and ATG3, forms LC3-II. This molecule is assimilated into phagophore and autophagosomal membranes, where LC3-II interacts with cargo receptors, which harbor LIRs [24]. DFCP1, zinc-finger; ECM, extracellular matrix; FYVE domain-containing protein 1; LC3, microtubule-associated protein light chain 3; LIRs, LC3-interacting motifs; PE: phosphatidylethanolamine ULK-1, Unc-51-like kinase 1; WIPIs, WD repeat domain phosphoinositide-interacting proteins