Fig. 1

An overview of signaling nexus of autophagy pathways. Phosphorylated AMP-activated kinase (AMPK) initiates induction of autophagy by phosphorylating (p in orange circle) ULK1 (a protein kinase) at Ser555, which then activates a class III PI 3-kinase (PI3K) via phosphorylation in the PI3K–ATG14L (ATG refers to an autophagy-related family of proteins) protein complexes. The activated PI3K–ATG14L complexes recruit the scaffold protein Beclin 1, dissociated from Beclin 1–BCL-2 complexes upon BCL-2 (member of family of proteins which regulate apoptosis) phosphorylation, to form a PI3K–ATG14L–BECLIN 1 complex. This complex joins together with a fragment of double membrane, and the activated PI3K in the complex produces the phospholipid PI₃P (phosphatidylinositol 3-phosphate) that activates WIPI1, a homolog of the yeast Atg18 protein, and begins to build a phagophore (also called the isolation membrane). To elongate the phagophore, ATG12–ATG5–ATG16–LC3-II complexes are needed. For this process, LC3, a central protein in the autophagy pathway, is cleaved by ATG4, resulting in LC-1, and the resultant LC3-I is then conjugated with phosphatidylethanolamine (PE) through ATG7 to become LC-II. The LC3-II now conjugates with the ATG12–ATG5–ATG16 complexes to form ATG12–ATG5–ATG16–LC3-II complexes. Finally, ATG12–ATG5–ATG16–LC3-II complexes are attached to an activated phagophore and begin to elongate the membrane. The elongated phagophore encloses cellular cargos, including protein aggregates and mitochondria, using the LC3-II residing in the luminal side of the phagophore, and LC3 adapter proteins, such as p62 and BNIP3 (BCL2/adenovirus E1B nineteen kDa interacting protein 3). Once cellular cargos are completely enclosed, an autophagsome (a spherical structure with double layer membrane) is formed and subsequently fused with a lysosome with the help of lysosome-associated membrane protein2 (LAMP2) and soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) proteins. Cargo materials are then processed by lysosomal proteases such as CATHEPSIN L and recycled. To enhance autophagic fluxes, lysosomal biosynthesis also occurs by upregulating a master transcription regulator of lysosomal biogenesis, transcription factor EB (TFEB), which is regulated by the modulation of the phosphorylation state. An activated CALCINEURIN, a calcium-dependent phosphatase, dephosphorylates TFEB and facilitates the translocation of TFEB to the nucleus, where TFEB promotes the transcription of lysosome-related proteins