The PI3K complex consists of Vps34, Vps15
, Atg6, and Atg14 in the yeast.
Positive regulators of autophagy include VPS34, VPS15
, UVRAG, ATG14, AMBRA1, HMGB1, and Bif-1, with AMBRA1 promoting autophagy as well as being involved in the nutrient-dependent localization of Beclin-1.
For example, the ULK1-ATG13-FIP200-ATG101 complex is responsible for the induction of autophagy [16, 17], the class III phosphatidylinositol (PtdIns) 3-kinase complex (BECN1, ATG14/ATG14L, VPS15, VPS34, and AMBRA1) is responsible for the initiation of the autophagosome [18, 19], and the ATG12-5-16 and LC3-II are responsible for the formation of autophagosome [20-22].
The active ULK1 complex and the class III phosphatidylinositol-3-phosphate (PtdIns3P) kinase complex, formed by BECN1, ATG14, VPS15, VPS34, and Ambra1, control the initiation of autophagosome, via PtdIns3P formation and WIPI recruitment.
ROS: reactive oxygen species; ATG101: autophagy-related 101; FIP200: FAK family kinase-interacting protein of 200 kDa; ULK: unc-51-like autophagy-activating kinase 1; ATG13: autophagy-related 13; ATG12: autophagy-related 12; ATG7: autophagy-related 7; ATG10: autophagy-related 10; ATG5: autophagy-related 5; ATG16: autophagy-related 16; ATG14: autophagy-related 14; mTOR: mammalian target of rapamycin; AMBRA1: autophagy/beclin-1 regulator 1; Vps15
: serine/threonine-protein kinase VPS15
; PI3K: phosphoinositide 3 kinase; LC3: microtubule-associated protein 1A/1B-light chain 3; WIPI: WD repeat domain phosphoinositide-interacting protein; DFCP1: double FYVE domain-containing protein.
This complex consists of a class III PI3K (VPS34), beclin 1, VPS15
, and ATG14L.
After Ulk1 complex activation, vesicle nucleation occurs via activation of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex, which comprises PtdIns3K, Beclin 1, Vps15
, and Atg14L.
Following the initiation, the vesicle nucleation is one the key processes in autophagy, in which phosphatidylinositol 3-kinase (PI3K) dependent activation and formation of complex composed of VPS15
, VPS34, VPS30, and ATG6/BECN1 (Beclin 1) proteins play a central role in vesicle formation.
Phagophore nucleation requires the formation of a complex consisting of the vacuolar protein sorting (VPS) 34, VPS15
, Beclin1, and the activating autophagy/beclin-1 regulator 1 (AMBRA1) ; in this process, B-cell lymphoma 2 (BCL-2) inhibits autophagy by binding Beclin1, while BCL-2-homology 3 (BH3-only) activates the VPS34 complex by displacement of the BCL-2 protein .
The vesicle nucleation process is executed by a protein complex whose core comprises the class III phosphatidylinositol-3-kinase (PI3Kc3 or VPS34) which catalyzes phosphorylation of phosphatidylinositol to phosphatidylinositol 3-phosphate; the PI3Kc3 regulatory subunit (p150 or VPS15
), a myristylated serine/threonine kinase that phosphorylates PI3Kc3 and recruits it to the membrane; and the BCL-2 interacting protein (Beclin 1 or ATG6), which appears to be a protein interaction hub.
As a member of Atg proteins, class III PI3K composes of a Vps15
regulatory subunit and a Vps34 catalytic subunit, which promote phosphatidylinositol (PI) conversion to phosphatidylinositol 3phosphate [PI(3)P] and then initiate autophagy [35-38].
Subsequent to translocation, ULK1 phosphorylates Beclin 1 (ser-14), which, together with Vps34 and Vps15
, forms class III phosphatidylinositol 3-kinase (PI3K) complex .