Fig. 2

Molecular mechanism of autophagy. There are generally five steps of autophagy which include initiation, elongation, nucleation, fusion and degradation [39]. Energy deprivation or cellular stress will generate cellular autophagy signals that activate the ULK1 kinase complex to activate the downstream AMBRA protein [16]. AMBRA then phosphorylates the class III PI3K to increase PIP3 level and this helps recruiting a number of autophagy related proteins like WIPI2, ATG16L1, ATG12, ATG5 and SQSTM1/p62 to the pre-autophagosome (PAS) [16]. As these essential proteins are being recruited, PAS elongates and the production of lipidated LC3-II helps the PAS to surround and enclose the substrate macromolecules to be digested [46]. When the nucleation process is completed, mature autophagosome is formed and it is ready to bind to the lysosome to form autolysosome [39]. Positive regulators of autophagy process include AMPK [54], PTEN [56], Bif-1 [58] and TFEB [59] while negative regulators of autophagy include Akt [56], mTORC1 [60] and Bcl-2 [57]