Table 1.

Significant genes in the mammalian autophagy pathway.

Gene	Important interactions	Protein function/characteristics
Formation of autophagosomes
ULK1 (ATG1)	Atg13, FIP200 (Atg17)	Ser/Thr kinase activity important for function; target(s) unknown. Downstream of mTOR signaling. Potentially involved in Atg9 cycling.
Beclin-1 (ATG6)	hVps34, Bcl-2/Bcl-xL, UVRAG	Structural regulator of class III PI3 kinase hVps34. Contains BH3-like domain that is down-regulatory when occupied.
hVPS34	Beclin-1, mTOR	Class III PI3 kinase; resulting PtdIns(3)Ps recruit Atg16L multimer/Atg18 to phagophore. Conflictingly activates mTor in response to amino acids.
ATG9	Atg2, Atg18	Transmembrane protein. Transits between phagophores and trans-Golgi/late endosomes. Possible role(s) in protein recycling and/or membrane transit.
ATG12	Atg5, Atg16L	Covalently bound to Atg5 via mechanism similar to ubquitination.
ATG7	LC3, Atg12	Functionally similar to E1 ubiquitin activating enzyme (E1-like). Activates C-terminal glycine of both Atg12 and LC3.
ATG10	Atg12, Atg5	Functionally similar to E2 ubiquitin conjugating enzyme (E2-like). Accepts activated Atg12 and conjugates to internal lysine of Atg5.
ATG5	Atg12, Atg16L	Covalently bound to Atg12; conjugation allows Atg5 to associate with Atg16L.
ATG16L	Atg5–Atg12	Associates with Atg12–Atg5 and dimerizes. Present on outer surface of expanding phagophore; aids membrane curvature and LC3 recruitment (E3-like). Recycled.
ATG4	LC3	Cysteine protease; exposes C-terminal glycine on LC3 prior to lipidation. Subsequently recycles LC3 from outer membrane of autophagosome.
ATG3	LC3, Atg7	Functionally similar to E2 ubiquitin conjugating enzyme (E2-like). Conjugates LC3 with phosphatidylethanolamine (PE) phospholipid.
MAP1LC3 (ATG8)	Atg4	Experimental marker of induction. Cytosolic form (LC3-I) conjugated to PE, becoming membrane-associated (LC3-II). Possible role(s) in membrane expansion, autophagosome transit, and lysosomal fusion. Partially recycled by Atg4.
Regulation of autophagy
PI3K (class I)		Produces PtdIns(3)p that activates the Akt/PKB-mTor pathway.
PTEN		Phosphatase that counteracts PI3K by dephosphorylating PtdIns(3)p.
AKT/PKB	PDK1, Tsc 2	Ser/Thr kinase. Activated by PDK1 in the presence of PtdIns(3)p. Inactivates Tsc 2.
REDD1/REDD2		Transcriptionally up-regulated in response to hypoxia. Inactivates mTor pathway.
AMPK	LKB1, Tsc2	Activates Tsc2, leading to the induction of autophagy when the AMP/ATP ratio is high.
TSC2	Tsc1, Rheb, Akt/PKB, AMPK	GTPase-activating protein (GAP) with Tsc1; inactivates Rheb. Akt/PKB interferes with function, as does Erk1/2. AMPK enhances activity.
Rheb	Tsc1/Tsc2, mTor	Small GTPase. Activates mTor via binding kinase domain in GTP-dependent fashion. Tsc1/Tsc2 GAP activity converts to inactive, GDP-bound form.
mTOR	Rheb, raptor, mLST8	Key regulator of cellular growth. Autophagy induced when mTor inactivated. Ser/Thr kinase. Forms two protein complexes; mTORC1 associated with autophagy.
Anti-apoptotic Bcl-2 family	Beclin-1	Inhibit autophagy via binding with BH3 motif on Beclin-1. JNK1-mediated phosphorylation disrupts interaction and associated inhibition.
BH3-only Bcl-2 family	Anti-apoptotic Bcl-2 family	Competitively bind with anti-apoptotic Bcl-2 family members, interfering with their association with Beclin-1. Stimulate autophagy.
JNK1	Anti-apoptotic Bcl-2 family	Phosphorylates anti-apoptotic Bcl-2 family members, inhibiting interaction with Beclin-1. Activity induces autophagy.
UVRAG	Bif-1, Beclin-1	Interacts with Beclin-1's coiled-coil domain, strengthening Beclin-1/hVps34 interactions; promotes autophagy. Possible additional role in lysosome fusion.
p53		Controversial/contradictory role(s) in autophagy. P53-dependent autophagy observed experimentally. However, cytosolic p53 is inhibitory (mechanism unknown).
DRAM		Transmembrane lysosomal protein transcriptionally induced by p53. Stimulates autophagy. Necessary for both p53-dependent autophagy and apoptosis.