| Functional role (autophagy step) | Molecular mechanism | Key interaction partners/complex | Key localization | Regulatory PTMs/regulators | Representative recent sources (URL; publication month/year) | Evidence notes/quantitative data |
|---|---|---|---|---|---|---|
| Autophagy initiation / phagophore nucleation | ATG14 is the autophagy-specific subunit of PI3KC3-C1 and helps activate VPS34 lipid kinase to generate PI3P needed for early autophagosome formation (pqac-00000002, pqac-00000003, pqac-00000004) | PI3KC3-C1 = VPS34/PIK3C3, VPS15/PIK3R4, BECN1, ATG14 (pqac-00000001, pqac-00000003) | ER-associated autophagosome formation sites / omegasomes (pqac-00000002, pqac-00000006) | Positive regulation by ULK1 phosphorylation; negative regulation by mTORC1 on ATG14-containing VPS34 complexes; AMPK-linked pathway effects are context-dependent (pqac-00000004, pqac-00000005) | Tabata et al., *Nature Communications* (https://doi.org/10.1038/s41467-024-51402-w; Aug 2024); Lee et al., *Biomolecules & Therapeutics* (https://doi.org/10.4062/biomolther.2024.094; Oct 2024); Park et al., *Nature Communications* (https://doi.org/10.1038/s41467-023-38401-z; May 2023) | Human PI3KC3-C1 described as a ~360 kDa 1:1:1:1 heterotetramer; catalytic domain is ~11% of complex mass, emphasizing regulatory/non-catalytic roles of subunits including ATG14 (pqac-00000003) |
| PI3P production downstream of ULK1 | ULK1 phosphorylates ATG14 at Ser29, which is required for VPS34 activation and PI3P production at autophagosome formation sites (pqac-00000001, pqac-00000003) | ULK1 complex functionally coupled to PI3KC3-C1 through ATG14 and BECN1 (pqac-00000001, pqac-00000004) | Autophagosome formation sites on ER/phagophore membranes (pqac-00000001, pqac-00000002) | ULK1 kinase activity; loss in ULK1/2 DKO or kinase-dead ULK1 blocks ATG14 Ser29 phosphorylation (pqac-00000001) | Tabata et al., *Nature Communications* (https://doi.org/10.1038/s41467-024-51402-w; Aug 2024); Park et al., *Nature Communications* (https://doi.org/10.1038/s41467-023-38401-z; May 2023) | Phospho-Ser29 was absent in ULK1/2 double-KO and kinase-dead ULK1 settings; WT ULK1 restored starvation-induced phosphorylation (pqac-00000001) |
| Membrane targeting and curvature sensing during early autophagosome biogenesis | ATG14 C-terminal BATS domain contains an amphiphilic helix and functions as a membrane curvature sensor; preferentially binds highly curved nascent isolation membranes and PI3P/PI(4,5)P-enriched membranes (pqac-00000006, pqac-00000009) | ATG14-containing PI3KC3-C1; Beclin1 recruitment to isolation membrane/ER (pqac-00000006) | Initiating isolation membrane, omegasome, tubular ER (pqac-00000006, pqac-00000009) | N-terminal cysteine-repeat sequence mediates ER targeting; membrane curvature and PI3P provide positive feedback for recruitment/activity (pqac-00000006, pqac-00000009) | Liu et al., *Cells* (https://doi.org/10.3390/cells12081132; Apr 2023); Lee et al., *Biomolecules & Therapeutics* (https://doi.org/10.4062/biomolther.2024.094; Oct 2024) | Review summarizes BATS as ~last 80 aa with a 19-aa amphipathic helix; ATG14 co-localizes with ATG16L1 and DFCP1 at omegasomes (pqac-00000006) |
| LC3 lipidation support downstream of PI3P | ATG14-dependent PI3KC3-C1 activity supports recruitment of WIPI2 and ATG2A, enabling efficient LC3 lipidation; complex II cannot substitute functionally in this assay (pqac-00000008, pqac-00000011) | PI3KC3-C1, WIPI2, ATG2A; distinguishes ATG14 complex I from UVRAG complex II (pqac-00000003, pqac-00000008) | ER-derived membranes / omegasome-associated early autophagic membranes (pqac-00000008, pqac-00000011) | Depends on VPS34 catalytic activity and ATG14 ALPS/BATS-like curvature-sensing element (pqac-00000008, pqac-00000011) | No 2023–2024 primary assay source in gathered context; supported by Brier et al., *Molecular Biology of the Cell* (https://doi.org/10.1091/mbc.e18-11-0743; Apr 2019) and discussed in later reviews (pqac-00000008, pqac-00000011) | In ATG14-knockout cytosol reconstitution, PI3KC3-C1 supported LC3 lipidation, whereas curvature-sensing/ALPS-defective derivatives failed to complement (pqac-00000008, pqac-00000011) |
| ER/omegasome targeting of the autophagy-initiation machinery | ATG14 is required for ER targeting of the class III PI3K complex and thereby for nucleation of PI3P-rich omegasomes (pqac-00000002, pqac-00000006, pqac-00000011) | BECN1-binding ATG14 subunit of PI3KC3-C1; mutually exclusive with UVRAG in complex II (pqac-00000003, pqac-00000006) | ER, omegasomes, early isolation membrane (pqac-00000002, pqac-00000006) | Competitive assembly with UVRAG affects pathway specificity between autophagy initiation and endolysosomal sorting (pqac-00000003, pqac-00000006) | Lee et al., *Biomolecules & Therapeutics* (https://doi.org/10.4062/biomolther.2024.094; Oct 2024); Liu et al., *Cells* (https://doi.org/10.3390/cells12081132; Apr 2023) | Complex I (ATG14-containing) is linked to initiation, whereas complex II (UVRAG-containing) functions in endolysosomal sorting/later autophagy stages (pqac-00000003) |
| Coupling upstream membrane delivery to PI3KC3-C1 activation | ULK1 palmitoylation by ZDHHC13 promotes ULK1 translocation and enhances phosphorylation of ATG14, increasing PI3P production and autophagy initiation (pqac-00000001, pqac-00000012) | ZDHHC13, ULK1, ATG14, ATG9A-associated membranes (pqac-00000001) | Golgi/ATG9A vesicle-linked pathway feeding autophagosome formation sites (pqac-00000001) | ULK1 palmitoylation; inhibitor 2-bromopalmitate suppresses ATG14 Ser29 phosphorylation (pqac-00000001, pqac-00000012) | Tabata et al., *Nature Communications* (https://doi.org/10.1038/s41467-024-51402-w; Aug 2024) | Reported colocalization values: endogenous ZDHHC13 with ATG9A membranes 12.7% and 62.0% in distinct measurements; palmitoylation-deficient ULK1 mutants showed markedly reduced ATG14 Ser29 phosphorylation (pqac-00000001) |
| Pharmacologic targeting relevance | ATG14’s BATS domain is a major membrane-binding determinant of PI3KC3-C1; reviews discuss VPS34 inhibitors and a Beclin1–ATG14L interaction inhibitor as tools/therapeutic leads for autophagy-initiation blockade (pqac-00000007, pqac-00000008) | PI3KC3-C1 / VPS34 pathway; Beclin1–ATG14 interface (pqac-00000007, pqac-00000008) | Autophagy-initiation machinery at omegasomes (pqac-00000007) | VPS34 inhibitors; Beclin1-ATG14L interaction inhibitor 1 mentioned in review context (pqac-00000007) | Lee et al., *Biomolecules & Therapeutics* (https://doi.org/10.4062/biomolther.2024.094; Oct 2024) | Gathered evidence supports pathway-level rather than ATG14-specific clinical implementation; no direct ATG14-targeted clinical trials were identified in the searched trials context (pqac-00000007) |


*Table: This table summarizes experimentally supported functions, mechanisms, localization, and regulation of human ATG14/ATG14L in autophagy initiation. It emphasizes recent 2023–2024 sources where available and includes quantitative findings from the gathered evidence.*