Affinage

ATG12

Ubiquitin-like protein ATG12 · UniProt O94817

Length
140 aa
Mass
15.1 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATG12 is a ubiquitin-like modifier central to autophagosome biogenesis that acts primarily through covalent conjugation to ATG5 and, in a distinct reaction, to ATG3 (PMID:20723759, PMID:16963840). The C-terminal ubiquitin-fold region of ATG12 is necessary and sufficient for ATG5 conjugation and autophagy, with conjugation occurring on a specific ATG5 lysine via the E1 enzyme ATG7, the E2 enzyme ATG10, and ATP, and stimulated in vitro by RNA (PMID:16874032, PMID:16963840, PMID:12482611). The resulting ATG12~ATG5 conjugate is the catalytic core of an E3-like enzyme: structural and biochemical work shows ATG12 docks onto ATG5 through a continuous conserved surface patch and presents a dedicated hydrophobic pocket (the AIM12 surface, structurally equivalent to the LC3 LIR pocket) that recruits the E2 enzyme ATG3, reorienting ATG3's catalytic cysteine toward a catalytic threonine to stimulate ATG8/LC3-PE lipidation (PMID:17986448, PMID:23202584, PMID:23503366, PMID:24191030, PMID:34193767). The conjugate associates with ATG16L1 to form a multimeric ATG12-ATG5-ATG16L1 complex that targets the autophagic isolation membrane and elongates it into a complete autophagosome (PMID:11897782, PMID:12665549, PMID:12672448); ATG16L1 stabilizes ATG5 against proteasomal degradation and is recruited to PtdIns(3)P-rich membranes by the effector WIPI2b (PMID:31636955, PMID:24954904). On membranes the ternary complex accelerates LC3/GABARAP lipidation and tethers vesicles while suppressing inter-vesicular fusion, acting as a rigid scaffold (PMID:36729310, PMID:23321721). Beyond canonical autophagy, ATG12 has conjugation-independent and alternative-conjugation roles: free ATG12 directly binds and inactivates the prosurvival proteins BCL-2 and MCL-1 via a BH3-like motif to promote mitochondrial apoptosis (PMID:22152474); the ATG12~ATG3 conjugate maintains mitochondrial homeostasis and, through interaction with the ESCRT protein Alix, governs basal autophagic flux and late-endosome function (PMID:20723759, PMID:25686249); the ATG12-ATG5 conjugate suppresses innate antiviral type I IFN signaling by binding the CARD domains of RIG-I and MAVS (PMID:17709747); and an ATG16L1-independent, TECPR1-containing complex drives unconventional LC3 lipidation and repair at damaged lysosomes (PMID:22342342, PMID:37381828).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 Medium

    Establishing how ATG12 is conjugated and assembled identified the E2 enzyme and the higher-order complex that the conjugate forms, defining the machinery of the conjugation system.

    Evidence Yeast two-hybrid, Co-IP, and gel filtration showing ATG10 as the E2 and ATG12-ATG5 association with ATG16 into a ~350 kDa complex

    PMID:11897782 PMID:12482611

    Open questions at the time
    • Did not resolve the structural basis of E2-substrate recognition
    • Functional role of ATG16 oligomerization in mammals not addressed
  2. 2003 Medium

    Defining where the conjugate acts and what its mammalian binding partners are localized the complex to the isolation membrane and identified ATG16L1 as the membrane-targeting scaffold.

    Evidence Biochemical fractionation, reciprocal Co-IP, deletion mutagenesis, and immunofluorescence in mouse cells; conjugation-deficient cell analysis

    PMID:12665549 PMID:12672448 PMID:12965207

    Open questions at the time
    • Mechanism of membrane targeting not defined at the molecular level
    • Did not establish how the complex stimulates lipidation
  3. 2005 Medium

    Dissecting ATG12 residues and reconstituting the system in plants separated the conjugation function from the downstream lipidation function and showed conservation of the pathway.

    Evidence Site-directed mutagenesis with parallel conjugation/autophagy readouts and crystallography of Arabidopsis ATG12 with genetic complementation

    PMID:16874032 PMID:16874047

    Open questions at the time
    • Functional assignment of the ATG12-unique hydrophobic patch was inferred, not mutated
    • How F154 enables ATG8-PE conjugation mechanistically unresolved
  4. 2007 High

    Reconstituting the reactions in vitro proved the ATG12-ATG5 conjugate is itself an E3-like enzyme that stimulates ATG3-mediated ATG8 lipidation and that conjugation can be rebuilt from purified components.

    Evidence In vitro ATG8 conjugation and ATG12-ATG5 reconstitution with purified proteins and liposomes; ATG5 lysine mutagenesis; RNA stimulatory factor identification

    PMID:16963840 PMID:17986448

    Open questions at the time
    • Structural basis of E3 activity not yet resolved
    • Physiological relevance of RNA stimulation in cells unclear
  5. 2007 High

    Testing the conjugate outside autophagy revealed a direct immunoregulatory function, showing ATG12-ATG5 dampens antiviral type I IFN signaling.

    Evidence Co-IP with RIG-I and IPS-1/MAVS CARD domains, Atg5/Atg7-KO MEFs with IFN-beta readouts, overexpression

    PMID:17709747

    Open questions at the time
    • Whether conjugate engagement of CARD domains is direct or bridged not fully resolved
    • In vivo immune consequences not established here
  6. 2010 High

    Discovery of a second ATG12 conjugate (ATG12~ATG3) separated from the ATG5 conjugate established a distinct, mitochondria-directed function for ATG12.

    Evidence Mass spectrometry, ATG3 lysine mutagenesis, in vitro conjugation, and KO/KD MEFs with mitochondrial mass and apoptosis readouts

    PMID:20723759

    Open questions at the time
    • Molecular target of the conjugate on mitochondria not identified
    • How ATG12~ATG3 controls mitochondrial mass mechanistically unknown
  7. 2011 High

    Showing free ATG12 acts via a BH3-like motif assigned a conjugation-independent pro-apoptotic role, distinguishing unconjugated ATG12 from the autophagy machinery.

    Evidence Co-IP with BCL-2 and MCL-1, computational docking validated by mutagenesis, KD/OE with BAX activation and cytochrome c readouts

    PMID:22152474

    Open questions at the time
    • Structural confirmation of the BH3-like motif binding not provided
    • Regulation of free ATG12 levels not addressed in this study
  8. 2011 Medium

    Vaccinia-induced ATG12~ATG3 conjugation uncoupled LC3 lipidation from autophagosome formation, showing alternative conjugation can drive non-canonical lipidation.

    Evidence Mass spectrometry, atg5-null and atg7-null MEFs, electron microscopy, autophagic flux assays

    PMID:22024753

    Open questions at the time
    • Viral factor inducing ATG12~ATG3 conjugation not identified
    • Single lab; functional purpose of the lipidation unclear
  9. 2012 High

    Crystal structures of the conjugate and the E2-substrate pair provided the structural mechanism of conjugation and E3 recruitment, explaining how ATG12 positions ATG3 without an external E3.

    Evidence X-ray crystallography of human and yeast ATG12-ATG5/ATG16L1 complexes and ATG10-ATG5, with mutagenesis and in vitro lipidation/kinetic assays

    PMID:22682742 PMID:23202584 PMID:23238393

    Open questions at the time
    • Did not capture the catalytic transition state of lipidation
    • Membrane context of the conjugate not in the structures
  10. 2012 High

    Identifying TECPR1 as a mutually exclusive partner of ATG16 and the IFN-gamma antiviral role extended the conjugate's functions to autophagosome-lysosome fusion and non-degradative antiviral defense.

    Evidence Co-IP, PtdIns(3)P pulldown, KD autophagy flux; and multiple KO macrophages with murine norovirus replication readouts

    PMID:22342342 PMID:22520467

    Open questions at the time
    • How TECPR1 and ATG16 selection is regulated not defined
    • Mechanism of IFN-gamma-induced suppression of viral replication complex unresolved
  11. 2013 High

    Mechanistic and membrane-binding studies revealed how the conjugate stimulates catalysis and how the ternary complex engages membranes, defining the catalytic and tethering logic of the E3.

    Evidence Biochemistry/mutagenesis of ATG3 catalytic residues and in vitro reconstitution with GUVs/liposomes plus yeast genetics

    PMID:23321721 PMID:23503366

    Open questions at the time
    • Regulation of membrane binding in cells not established
    • How fusion suppression is reconciled with autophagosome maturation unclear
  12. 2013 High

    Structural mapping of the ATG12-ATG3 interface defined the dedicated E2-recruitment surface on ATG12 analogous to the LC3 LIR pocket.

    Evidence Crystal structure of human ATG12 bound to an ATG3 fragment with mutagenesis and LC3 lipidation assays

    PMID:24191030

    Open questions at the time
    • Did not address how this interface is regulated during the catalytic cycle
  13. 2014 Medium

    Identifying WIPI2b as the upstream PtdIns(3)P effector and characterizing free ATG12 turnover linked complex recruitment to membrane lipids and to proteasomal control of ATG12 abundance.

    Evidence Interaction mapping, ATG16L1 mutant rescue in KO MEFs, Salmonella clearance; in vivo ubiquitination and pulse-chase stability assays

    PMID:24954904 PMID:25629932

    Open questions at the time
    • E3 ligase for free ATG12 ubiquitination not identified
    • How WIPI2b binding is coordinated with ATG5 stabilization unclear
  14. 2015 Medium

    Linking the ATG12~ATG3 conjugate to Alix/ESCRT and revealing distinct ATG12 functions in neurons established conjugate- and tissue-specific roles separate from canonical autophagy.

    Evidence Co-IP, KO cell lines with endosome/exosome/viral budding and basal flux readouts; ATG12 vs ATG5 conditional KO mice with metabolic phenotyping

    PMID:25585051 PMID:25686249

    Open questions at the time
    • Molecular basis of ATG12~ATG3-Alix coupling not defined
    • The non-autophagic ATG12 function in POMC neurons not identified molecularly
  15. 2019 Medium

    Defining stabilization and competition mechanisms clarified how conjugate flux toward functional complex is controlled and revealed additional metabolic and parasite-derived variations.

    Evidence Co-IP/mutagenesis/ubiquitination assays (ATG16L1 vs ATG16L2), ATG12-KO cancer cell metabolomics and respirometry, and evolutionary/biochemical analysis of non-covalent ATG12-ATG5 complexes

    PMID:30911187 PMID:31636955 PMID:31844253

    Open questions at the time
    • In vivo relevance of ATG16L2 dominant-negative competition unclear
    • Mechanism connecting ATG12 to mitochondrial biogenesis not defined
  16. 2023 High

    Reconstituting the full human ternary complex, defining TECPR1-driven lysosomal repair, and developing an interface inhibitor advanced both the membrane mechanism and pharmacological targeting of ATG12 conjugates.

    Evidence In vitro lipidation/tethering/lipid-mixing with purified ATG12-ATG5-ATG16L1; ATG16L1/TECPR1 double-KO lysosomal damage assays; PCA screen identifying an ATG12-ATG3 interface inhibitor

    PMID:36729310 PMID:37184247 PMID:37381828

    Open questions at the time
    • How the scaffold both tethers and suppresses fusion in vivo unresolved
    • Selectivity and in vivo efficacy of the inhibitor not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how cells partition ATG12 among its covalent ATG5 conjugate, its ATG3 conjugate, and free pools to switch between autophagy, mitochondrial apoptosis, endosomal function, and immune regulation.
  • No defined regulatory mechanism governing conjugate-vs-free ATG12 balance
  • Molecular targets of the ATG12~ATG3 conjugate on mitochondria unidentified
  • In vivo significance of non-autophagic ATG12 functions largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0031386 protein tag activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 2 GO:0005764 lysosome 2 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1
Pathway
R-HSA-9612973 Autophagy 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
ATG10ATG16L1ATG3ATG5ATG7BCL2PDCD6IPTECPR1
Complex memberships
ATG12-ATG5-ATG16L1 complexATG12-ATG5-TECPR1 complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 The ATG12-ATG5 conjugate, but not unconjugated ATG12 or ATG5, acts as an E3-like enzyme that promotes ATG8-PE (phosphatidylethanolamine) conjugation by stimulating the E2 activity of ATG3; the conjugate interacts with both ATG3 and PE-containing liposomes to facilitate protein-lipid conjugation. In vitro ATG8 conjugation reconstitution assay with purified proteins and liposomes; E3-like activity confirmed by showing conjugate-dependent transfer of ATG8 from ATG3 to PE The Journal of biological chemistry High 17986448
2002 The ATG12-ATG5 conjugate associates with ATG16 (Apg16) to form an ~350 kDa multimeric complex through ATG16 homo-oligomerization; this complex formation is required for autophagy in yeast. Yeast two-hybrid, co-immunoprecipitation, gel filtration, in vivo oligomerization control system; autophagy activity measured by Cvt pathway and bulk degradation assays The Journal of biological chemistry High 11897782
2003 The mouse ATG12-ATG5 conjugate forms an ~800 kDa complex with ATG16L1, a novel WD-repeat protein; ATG16L1 interacts with ATG5 (not requiring ATG12), self-oligomerizes independent of its WD-repeat domain, and the complex localizes to the autophagic isolation membrane during autophagosome formation. Membrane targeting of ATG16L1 requires ATG5 but not ATG12. Biochemical fractionation, co-immunoprecipitation, deletion mutagenesis, immunofluorescence microscopy of isolation membrane Journal of cell science High 12665549
2012 Crystal structure of the human ATG12~ATG5 conjugate bound to the N-terminal region of ATG16L1 shows ATG12 docking onto ATG5 via conserved residues forming a continuous surface patch; ATG12 provides a distinct surface for high-affinity binding of the E2 enzyme ATG3, and mutagenesis of the ATG12-ATG5 interface and continuous patch impairs E3 activity. X-ray crystallography; mutagenesis of interface residues; in vitro E3/LC3 lipidation activity assay; binding affinity measurements Nature structural & molecular biology High 23202584
2012 Crystal structure of the yeast ATG12-ATG5 conjugate shows ATG12 fixes its position on ATG5 via isopeptide linkage plus hydrophobic/hydrophilic interactions without inducing conformational change in ATG5; ATG12 functions as a binding module for ATG3 to facilitate ATG8 lipidation. X-ray crystallography; structural comparison with unmodified ATG5; mutational analysis of ATG3-binding surface EMBO reports High 23238393
2013 The ATG12-ATG5 conjugate enhances ATG3 E2 activity by rearranging ATG3's catalytic cysteine residue toward a catalytic threonine (unusual for E2 enzymes), thereby stimulating ATG8-PE conjugation; ATG12-ATG5 acts as a new type of E3 by inducing this reorientation. Biochemical analyses with yeast proteins informed by structural data; mutagenesis of ATG3 catalytic residues; in vitro ATG8 lipidation assay Nature structural & molecular biology High 23503366
2013 ATG12 recruits the E2 enzyme ATG3 through a specific surface on ATG12 exclusive to this protein; crystal structure of human ATG12 bound to a 13-residue ATG3 fragment (forming a short β-strand then α-helix) identifies four critical ATG3 residues; the ATG12 binding pocket corresponds structurally to the LC3-interacting region (LIR) pocket of LC3. Crystal structure of ATG12 minimal E3 complexed with ATG3 binding fragment; mutagenesis of ATG3 contact residues; LC3 lipidation assay Proceedings of the National Academy of Sciences of the United States of America High 24191030
2010 ATG12 is covalently conjugated to ATG3 (the E2-like enzyme for LC3 lipidation) on a single lysine; this conjugation requires ATG7 as E1 and ATG3 autocatalytic activity as E2. The ATG12-ATG3 complex does not affect starvation-induced autophagy but is required for mitochondrial homeostasis, and loss of ATG12-ATG3 expands mitochondrial mass and inhibits mitochondria-dependent cell death. Mass spectrometry identification; mutagenesis of ATG3 lysine; in vitro conjugation assay; KO/KD MEFs with mitochondrial mass and apoptosis readouts Cell High 20723759
2015 The ATG12-ATG3 conjugate interacts with the ESCRT-associated protein Alix (PDCD6IP) and controls Alix-dependent processes including late endosome distribution, exosome biogenesis, and viral budding; ATG12-ATG3 and Alix are both required for efficient basal (but not starvation-induced) autophagic flux; cells lacking ATG12-ATG3 accumulate perinuclear late endosomes and have impaired endolysosomal trafficking. Co-immunoprecipitation; KO cell lines; endosome distribution assay; exosome and viral budding assays; autophagy flux measurement Nature cell biology High 25686249
2011 Free (unconjugated) ATG12 directly binds and inactivates prosurvival BCL-2 family members BCL-2 and MCL-1 via a unique BH3-like motif, acting as a positive mediator of mitochondrial apoptosis independently of ATG5 or ATG3 conjugation; knockdown of ATG12 inhibited BAX activation and cytochrome c release. Co-immunoprecipitation; computational docking to identify BH3-like motif; mutagenesis; KD/OE with apoptosis readouts (BAX activation, cytochrome c release) Molecular cell High 22152474
2012 TECPR1 binds to the ATG12-ATG5 conjugate and PtdIns(3)P to promote autophagosome-lysosome fusion; TECPR1 and ATG16 form mutually exclusive complexes with ATG12-ATG5; TECPR1 binds PtdIns(3)P only upon association with ATG12-ATG5; TECPR1 recruits ATG5 to autolysosome membranes and its loss blocks autophagic degradation. Co-immunoprecipitation; PtdIns(3)P pulldown; KD with autophagy flux (GFP-mRFP-LC3) and p62/LC3-II accumulation readouts; fluorescence microscopy Molecular cell High 22342342
2002 Mouse ATG10 is the E2-like enzyme for ATG12 conjugation to ATG5; ATG10 mediates the conjugation reaction between mouse ATG12 and ATG5, and interacts with ATG12 in vivo in HeLa cells. Yeast two-hybrid screen; conjugation-mediated yeast two-hybrid assay; co-immunoprecipitation from HeLa cells FEBS letters Medium 12482611
2012 ATG10 directly recognizes ATG5 (particularly its C-terminal ubiquitin-like domain) through characteristic accessory β-strands; Tyr56 and Asn114 of ATG10 orient the ATG5 lysine for the conjugation reaction; this E2-substrate recognition enables ATG12-ATG5 conjugation without a specific E3 enzyme. Solution NMR and X-ray crystal structures of ATG10 and ATG5; mutagenesis; crosslinking experiments; kinetic analysis Structure High 22682742
2005 The C-terminal ubiquitin-fold region of ATG12 is necessary and sufficient for both ATG5 conjugation and autophagy; Y149 is required for conjugation by ATG10, while F154 (hydrophobic residue) is required for ATG8-PE conjugation and autophagosome formation without affecting ATG12-ATG5 conjugate formation; F154 is critical for assembly of the functional ATG12-ATG5·ATG16 complex. C-terminal deletion analysis; site-directed mutagenesis; in vivo conjugation assays; autophagy assays; gel filtration analysis of complex assembly Autophagy High 16874032
2005 The ATG12 conjugation system exists in Arabidopsis and is essential for plant autophagy; the crystal structure of Arabidopsis ATG12 reveals a ubiquitin fold with two types of hydrophobic surface patches—one shared with ATG8 orthologs (proposed for conjugation/ATG7 interaction) and one unique to ATG12 orthologs (proposed for ATG12-specific functions). X-ray crystallography at 1.8 Å; genetic complementation in yeast; structural comparison Autophagy Medium 16874047
2007 The ATG5-ATG12 conjugate negatively regulates innate antiviral type I IFN production by directly associating with RIG-I and IPS-1 (MAVS) through their CARD domains; overexpression of ATG5 or ATG12 (forming the conjugate) suppressed immunostimulatory RNA-mediated IFN-β signaling. Co-immunoprecipitation of ATG5-ATG12 conjugate with RIG-I and IPS-1; Atg5-KO and Atg7-KO MEFs with IFN production readouts; overexpression experiments Proceedings of the National Academy of Sciences of the United States of America High 17709747
2013 ATG5 directly binds membranes and this binding is negatively regulated by ATG12 conjugation but activated by ATG16; membrane binding by the ATG12-ATG5-ATG16 complex is required for efficient ATG8 lipidation; the complex also tethers vesicles in an ATG8-independent manner; in yeast, ATG5 membrane binding is not required for PAS recruitment but is essential for efficient autophagy prior to ATG8 lipidation. In vitro reconstitution with purified proteins, giant unilamellar vesicles (GUVs), and small liposomes; yeast genetics (point mutants); membrane binding assays Autophagy High 23321721
2007 Mammalian ATG12-ATG5 conjugation can be reconstituted in vitro using purified recombinant proteins; ATG7 (E1), ATG10 (E2), and ATP are essential for the reaction; mutation of the specific ATG5 lysine abrogates conjugation; RNA (ribosomal RNA component) potently stimulates ATG12-ATG5 conjugation in vitro. In vitro reconstitution with purified recombinant proteins; site-directed mutagenesis of ATG5 lysine; biochemical fractionation to identify stimulating activity; RNA/ribosome characterization Autophagy High 16963840
2014 WIPI2b directly binds ATG16L1 and functions as a PtdIns(3)P effector upstream of ATG16L1, recruiting the ATG12-5-16L1 complex to autophagosome formation sites; WIPI2b recruitment is required for LC3 conjugation, starvation-induced autophagy, and autophagic clearance of Salmonella. Identification of WIPI interacting partners; mutation experiments; ectopic membrane localization of WIPI2b; ATG16L1 mutant rescue in KO MEFs; Salmonella clearance assay Molecular cell High 24954904
2014 Free ATG12 (unconjugated) is highly unstable and rapidly degraded by the proteasome via direct ubiquitination; in contrast, the ATG12-ATG5 conjugate is stable; accumulation of free ATG12 upon proteasome inhibition contributes to proteasome inhibitor-mediated apoptosis. Proteasome inhibitor experiments; in vivo ubiquitination assay; pulse-chase protein stability assay; apoptosis readouts Autophagy Medium 25629932
2019 ATG16L1 protects free ATG5 from ubiquitin-proteasomal degradation by binding to it, thereby promoting ATG12-ATG5 conjugation over ubiquitination; the resulting ATG12-ATG5 conjugate displays enhanced affinity for ATG16L1, fully stabilizing the ATG12-ATG5-ATG16L1 complex; ATG16L2 acts as a dominant-negative by competing with ATG16L1 for ATG5 binding, enabling ATG12-ATG5 formation but blocking ATG16L1 incorporation and autophagy. Co-immunoprecipitation; mutagenesis of ATG16L1-binding pocket in ATG5; ubiquitination assays; proteasomal degradation assays; rescue experiments in KO cells Cell discovery Medium 31636955
2019 In apicomplexan parasites (Plasmodium, Toxoplasma) and some yeasts lacking ATG10 and the C-terminal glycine of ATG12, ATG12 forms a non-covalent complex with ATG5 instead of the canonical covalent isopeptide bond; this non-covalent ATG12-ATG5 complex retains the ability to facilitate ATG8-PE conjugation, demonstrating that covalent conjugation can evolve to non-covalent interaction. Genetic and biochemical analysis; identification of organisms lacking ATG10; in vitro/in vivo ATG8 lipidation assays with non-covalent complex Nature structural & molecular biology High 30911187
2023 Upon lysosomal membrane damage, TECPR1 forms an alternative E3-like complex with ATG12-ATG5 (independent of ATG16L1) to regulate unconventional LC3 lipidation at damaged lysosomes; TECPR1 is recruited to damaged membranes via its N-terminal dysferlin domain interacting with sphingomyelin; this complex promotes lysosomal repair upstream of galectin and lysophagy. KO cell lines (ATG16L1/TECPR1 double KO); lysosomal damage assay; LC3 lipidation assay; fluorescence microscopy; epistasis analysis EMBO reports High 37381828
2003 The ATG12-ATG5 conjugate localizes to elongating autophagic isolation membranes; ATG12 conjugation to ATG5 is required for elongation of the isolation membrane to form a complete autophagosome in mammalian cells. Immunofluorescence microscopy; subcellular fractionation; genetic loss-of-function (conjugation-deficient cells) The international journal of biochemistry & cell biology Medium 12672448
2012 The ATG5-ATG12/ATG16L1 complex is required for IFNγ-mediated antiviral defense against murine norovirus, acting through a non-degradative, non-autophagic mechanism; IFNγ via ATG5-ATG12/ATG16L1 inhibits formation of the membranous viral replication complex where ATG16L1 localizes; this function does not require ATG8 processing by ATG4B or lysosomal fusion. Atg5-KO, Atg7-KO, Atg16L1-KO macrophages; viral replication assays; localization of ATG16L1 to viral replication complex by microscopy; pharmacological inhibitor controls Cell host & microbe High 22520467
2015 ATG12 has distinct functions from ATG5 in POMC neurons: mice lacking ATG12 (but not ATG5) in POMC neurons exhibit accelerated weight gain, adiposity, glucose intolerance, hyperphagia, and reduced leptin sensitivity on high-fat diet; both deletions render neurons autophagy-deficient, indicating ATG12 has non-autophagic functions in POMC neurons. Conditional neuron-specific KO mice (ATG12 and ATG5 separately); metabolic phenotyping; autophagy assays in neurons; leptin sensitivity measurements Autophagy Medium 25585051
2019 ATG12 deficiency in cancer cells causes oncotic cell death associated with diminished mitochondrial biogenesis, reduced β-oxidation, glycolysis, and TCA cycle activity; ATG12 is partially localized to mitochondria in normal cells; loss of ATG12 reduces mitochondrial DNA content and multiple mitochondria-localizing proteins. ATG12-KO cancer cells; untargeted metabolomics; Seahorse respirometry; mitochondrial DNA quantification; mitochondrial protein profiling; mouse xenograft experiments; subcellular fractionation Cell death and differentiation Medium 31844253
2011 Vaccinia virus infection induces direct conjugation of ATG12 to ATG3 (not the canonical ATG5), resulting in massive ATG5/ATG7-independent LC3 lipidation but complete absence of autophagosome formation and autophagic flux; ATG3 is required for vaccinia-induced LC3 lipidation, but neither ATG3 nor LC3 lipidation is required for viral membrane biogenesis or replication. Mass spectrometry; immunoblotting; atg5-null and atg7-null MEFs; electron microscopy; autophagic flux assay Autophagy Medium 22024753
2014 Caveolin-1 (Cav-1) physically interacts with ATG5, ATG12, and the ATG12-ATG5 active complex in lung epithelial cells; Cav-1 competitively suppresses ATG12-ATG5 complex formation and autophagy; mutation of the Cav-1 binding motif on ATG12 disrupts interaction and augments autophagy. Co-immunoprecipitation; KD/overexpression; Cav-1 binding motif mutation on ATG12; autophagy flux assays American journal of physiology. Lung cellular and molecular physiology Medium 24727585
2017 FGFR3 directly interacts with the ATG12-ATG5 conjugate by binding to ATG5 and decreases ATG12-ATG5 conjugate protein levels, thereby inhibiting autophagic activity in chondrocytes; this mechanism contributes to achondroplasia pathogenesis. Co-immunoprecipitation; in vitro chondrogenic differentiation assay; embryonic bone culture; ATG5 overexpression rescue; autophagy assays Autophagy Medium 26491898
2017 RAS reduces ATG12 protein levels in colon cancer cells by accelerating its proteasomal degradation via the MEK-ERK1/2 kinase pathway; ATG12 loss promotes survival of oncogenic RAS-carrying malignant cells; the ability of ATG12 to kill these cells does not require covalent binding to ATG5 or other proteins. Proteasome inhibitor treatment; MEK inhibitor; ERK1/2 inhibitor; ATG12 overexpression; apoptosis and cell death assays Autophagy Medium 28933585
2021 ATG12-ATG5-ATG16L1 (E3-like complex) increases and accelerates LC3/GABARAP lipidation and subsequent vesicle tethering in vitro, but hampers LC3/GABARAP capacity to induce inter-vesicular lipid mixing/fusion, presumably by forming a rigid scaffold on the vesicle surface. Reconstitution of lipidation of six LC3/GABARAP family members with purified full-length ATG12-ATG5-ATG16L1 complex; vesicle tethering and lipid-mixing assays Cellular and molecular life sciences : CMLS High 36729310
2021 The plant ATG12b recognizes an Asp-Met motif (AIM12) in ATG3 via a hydrophobic pocket and basic residue on ATG12; crystal structure of plant ATG12b-ATG3 binding fragment complex confirms this recognition mode is similar to human ATG12-ATG3, defining a conserved ATG12-interacting motif (AIM12) for E2-E3 interaction. X-ray crystallography of plant ATG12b-ATG3 complex; mutagenesis of Asp-Met motif; complex formation assay Biological & pharmaceutical bulletin High 34193767
2019 BIRC5/Survivin physically binds the ATG12-ATG5 conjugate and prevents formation of the ATG12-ATG5-ATG16L1 complex; under serum deprivation, BIRC5 dissociates from ATG12-ATG5 allowing autophagy upregulation; BIRC5 also negatively modulates ATG7 protein stability. Co-immunoprecipitation; proximity ligation assay; KD/OE in multiple cancer cell lines and MEFs; autophagy flux measurements Autophagy Medium 31612776
2003 The C-terminal 17 amino acids of ATG7 (Apg7) are essential for ATG8 lipidation but not for ATG12 conjugation to ATG5; Apg7ΔC17 still interacts with ATG8, ATG12, and ATG3, and dimerizes normally, indicating these residues play a specific role in ATG8 lipidation distinct from ATG12 conjugation. Sequential C-terminal deletions of ATG7; yeast Cvt pathway and autophagy assays; co-immunoprecipitation; ATG8 lipidation and ATG12 conjugation assays FEBS letters Medium 12965207
2023 A small-molecule inhibitor (compound #189) identified by high-throughput PCA screen selectively disrupts the ATG12-ATG3 protein-protein interaction interface, inhibits autophagosome formation (GFP-LC3 puncta, IC50 ~9.3 μM), selectively kills autophagy-addicted tumor cells, and inhibits IL-1β secretion by macrophages. Protein-fragment complementation assay (PCA) screen of 41,161 compounds; GFP-LC3 puncta formation assay; selective tumor cell killing assay; IL-1β secretion assay Autophagy Medium 37184247

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. The Journal of biological chemistry 900 17986448
2014 WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Molecular cell 706 24954904
2003 Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. Journal of cell science 631 12665549
2008 The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. 'Protein modifications: beyond the usual suspects' review series. EMBO reports 610 18704115
2007 The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proceedings of the National Academy of Sciences of the United States of America 491 17709747
2002 Formation of the approximately 350-kDa Apg12-Apg5.Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast. The Journal of biological chemistry 370 11897782
2012 Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. Nature structural & molecular biology 357 23202584
2015 ATG12-ATG3 interacts with Alix to promote basal autophagic flux and late endosome function. Nature cell biology 259 25686249
2010 ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell 241 20723759
2011 The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis. Molecular cell 240 22152474
2013 Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation. Autophagy 239 23321721
2009 Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability. The Journal of pathology 229 19197948
2012 Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. Cell host & microbe 210 22520467
2015 miR-23b-3p regulates the chemoresistance of gastric cancer cells by targeting ATG12 and HMGB2. Cell death & disease 191 25996293
2012 A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate. Molecular cell 175 22342342
2014 Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression. Autophagy 130 24589849
2013 Atg12-Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site. Nature structural & molecular biology 129 23503366
2012 Structure of the Atg12-Atg5 conjugate reveals a platform for stimulating Atg8-PE conjugation. EMBO reports 128 23238393
2019 BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. Autophagy 110 31612776
2018 Inhibition of ATG12-mediated autophagy by miR-214 enhances radiosensitivity in colorectal cancer. Oncogenesis 109 29459645
2003 Role of the Apg12 conjugation system in mammalian autophagy. The international journal of biochemistry & cell biology 100 12672448
2020 Long non-coding RNA HOTAIR knockdown enhances radiosensitivity through regulating microRNA-93/ATG12 axis in colorectal cancer. Cell death & disease 98 32144238
2017 Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth. Cell death & disease 96 28182000
2005 The crystal structure of plant ATG12 and its biological implication in autophagy. Autophagy 96 16874047
2018 MicroRNA-128a represses chondrocyte autophagy and exacerbates knee osteoarthritis by disrupting Atg12. Cell death & disease 93 30206206
2013 Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12. Proceedings of the National Academy of Sciences of the United States of America 89 24191030
2015 Loss of Atg12, but not Atg5, in pro-opiomelanocortin neurons exacerbates diet-induced obesity. Autophagy 86 25585051
2009 Characterization of unusual families of ATG8-like proteins and ATG12 in the protozoan parasite Leishmania major. Autophagy 85 19066473
2014 Interaction of caveolin-1 with ATG12-ATG5 system suppresses autophagy in lung epithelial cells. American journal of physiology. Lung cellular and molecular physiology 80 24727585
2017 Optineurin promotes autophagosome formation by recruiting the autophagy-related Atg12-5-16L1 complex to phagophores containing the Wipi2 protein. The Journal of biological chemistry 79 29133525
2011 Atg16L2, a novel isoform of mammalian Atg16L that is not essential for canonical autophagy despite forming an Atg12–5-16L2 complex. Autophagy 79 22082872
2019 Toward the function of mammalian ATG12-ATG5-ATG16L1 complex in autophagy and related processes. Autophagy 77 31122169
2017 Foot-and-mouth disease virus infection suppresses autophagy and NF-кB antiviral responses via degradation of ATG5-ATG12 by 3Cpro. Cell death & disease 67 28102839
2012 Structural insights into Atg10-mediated formation of the autophagy-essential Atg12-Atg5 conjugate. Structure (London, England : 1993) 63 22682742
2016 miR-23b improves cognitive impairments in traumatic brain injury by targeting ATG12-mediated neuronal autophagy. Behavioural brain research 59 27630106
2005 Structure-function relationship of Atg12, a ubiquitin-like modifier essential for autophagy. Autophagy 59 16874032
2019 Long noncoding RNA HAGLROS promotes cell proliferation, inhibits apoptosis and enhances autophagy via regulating miR-5095/ATG12 axis in hepatocellular carcinoma cells. International immunopharmacology 56 31082725
2023 An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes. EMBO reports 54 37381828
2019 ATG5 cancer mutations and alternative mRNA splicing reveal a conjugation switch that regulates ATG12-ATG5-ATG16L1 complex assembly and autophagy. Cell discovery 54 31636955
2015 FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia. Autophagy 53 26491898
2014 Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity. Autophagy 50 25629932
2023 Effect of ATG12-ATG5-ATG16L1 autophagy E3-like complex on the ability of LC3/GABARAP proteins to induce vesicle tethering and fusion. Cellular and molecular life sciences : CMLS 49 36729310
2020 Upregulation of KCNQ1OT1 promotes resistance to stereotactic body radiotherapy in lung adenocarcinoma by inducing ATG5/ATG12-mediated autophagy via miR-372-3p. Cell death & disease 48 33082306
2015 ATG12-ATG3 connects basal autophagy and late endosome function. Autophagy 46 25998418
2019 Evolution from covalent conjugation to non-covalent interaction in the ubiquitin-like ATG12 system. Nature structural & molecular biology 45 30911187
2007 Stimulation of ATG12-ATG5 conjugation by ribonucleic acid. Autophagy 45 16963840
2020 SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12. Cell death & disease 44 31988284
2002 Mouse Apg10 as an Apg12-conjugating enzyme: analysis by the conjugation-mediated yeast two-hybrid method. FEBS letters 43 12482611
2020 PTBP3 promotes malignancy and hypoxia-induced chemoresistance in pancreatic cancer cells by ATG12 up-regulation. Journal of cellular and molecular medicine 40 31989778
2016 miR-30b inhibits autophagy to alleviate hepatic ischemia-reperfusion injury via decreasing the Atg12-Atg5 conjugate. World journal of gastroenterology 35 27182160
2018 Ambra1 modulates the sensitivity of breast cancer cells to epirubicin by regulating autophagy via ATG12. Cancer science 32 30027574
2023 Circular RNA circPOFUT1 enhances malignant phenotypes and autophagy-associated chemoresistance via sequestrating miR-488-3p to activate the PLAG1-ATG12 axis in gastric cancer. Cell death & disease 30 36624091
2021 Adaptor SH3BGRL drives autophagy-mediated chemoresistance through promoting PIK3C3 translation and ATG12 stability in breast cancers. Autophagy 30 34870550
2019 LncRNA HCG11 accelerates the progression of hepatocellular carcinoma via miR-26a-5p/ATG12 axis. European review for medical and pharmacological sciences 28 31858580
2011 Vaccinia virus leads to ATG12–ATG3 conjugation and deficiency in autophagosome formation. Autophagy 28 22024753
2021 LncRNA KCNQ1OT1 as a miR-26a-5p sponge regulates ATG12-mediated cardiomyocyte autophagy and aggravates myocardial infarction. International journal of cardiology 27 34089766
2018 Inhibition of LCMR1 and ATG12 by demethylation-activated miR-570-3p is involved in the anti-metastasis effects of metformin on human osteosarcoma. Cell death & disease 26 29795113
2019 ATG12 deficiency leads to tumor cell oncosis owing to diminished mitochondrial biogenesis and reduced cellular bioenergetics. Cell death and differentiation 25 31844253
2022 Apicoplast biogenesis mediated by ATG8 requires the ATG12-ATG5-ATG16L and SNAP29 complexes in Toxoplasma gondii. Autophagy 24 36095096
2018 miR‑23a downregulation modulates the inflammatory response by targeting ATG12‑mediated autophagy. Molecular medicine reports 24 29845275
2022 Danhong injection alleviates cerebral ischemia-reperfusion injury by inhibiting autophagy through miRNA-132-3p/ATG12 signal axis. Journal of ethnopharmacology 22 36115599
2021 LncRNA OIP5-AS1 Promotes the Autophagy-Related Imatinib Resistance in Chronic Myeloid Leukemia Cells by Regulating miR-30e-5p/ATG12 Axis. Technology in cancer research & treatment 22 34723728
2016 Increased ATG5-ATG12 in hepatitis B virus-associated hepatocellular carcinoma and their role in apoptosis. World journal of gastroenterology 22 27729742
2007 Mitochondrial DNA deletions and chloramphenicol treatment stimulate the autophagic transcript ATG12. Autophagy 22 17457038
2007 Cloning and characterization of an autophagy-related gene, ATG12, from the three-host tick Haemaphysalis longicornis. Insect biochemistry and molecular biology 22 17681237
2022 DJ-1 activates the Atg5-Atg12-Atg16L1 complex via Sirt1 to influence microglial polarization and alleviate cerebral ischemia/reperfusion-induced inflammatory injury. Neurochemistry international 21 35429577
2020 miR-30a-3p inhibits renal cancer cell invasion and metastasis through targeting ATG12. Translational andrology and urology 20 32420171
2017 Novel and functional ATG12 gene variants in sporadic Parkinson's disease. Neuroscience letters 19 28229934
2020 Functional Characterisation of the Autophagy ATG12~5/16 Complex in Dictyostelium discoideum. Cells 18 32397394
2019 Functional Characterization of Ubiquitin-Like Core Autophagy Protein ATG12 in Dictyostelium discoideum. Cells 18 30669443
2017 Mir505-3p regulates axonal development via inhibiting the autophagy pathway by targeting Atg12. Autophagy 18 28820282
2018 Atg12-Atg3 Coordinates Basal Autophagy, Endolysosomal Trafficking, and Exosome Release. Molecular & cellular oncology 17 30263931
2018 Blocking LC3 lipidation and ATG12 conjugation reactions by ATG7 mutant protein containing C572S. Biochemical and biophysical research communications 16 30503495
2017 Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells. Autophagy 15 28933585
2021 Erb-b2 Receptor Tyrosine Kinase 2 (ERBB2) Promotes ATG12-Dependent Autophagy Contributing to Treatment Resistance of Breast Cancer Cells. Cancers 14 33801244
2018 Induction of mitophagy in the HEI-OC1 auditory cell line and activation of the Atg12/LC3 pathway in the organ of Corti. Hearing research 14 29352609
2003 The carboxyl terminal 17 amino acids within Apg7 are essential for Apg8 lipidation, but not for Apg12 conjugation. FEBS letters 14 12965207
2022 Ginsenoside Rg1 suppresses paraquat-induced epithelial cell senescence by enhancing autophagy in an ATG12-dependent manner. Environmental toxicology 13 35657166
2018 ATG12 expression quantitative trait loci associated with head and neck squamous cell carcinoma risk in a Chinese Han population. Molecular carcinogenesis 13 29637616
2023 Vesicle tethering and fusion promoted by LC3/GABARAP proteins is modulated by the ATG12-ATG5-ATG16L1 complex. Autophagy 12 37062893
2023 Identifying a selective inhibitor of autophagy that targets ATG12-ATG3 protein-protein interaction. Autophagy 12 37184247
2022 LncRNA DDX11-AS1 Promotes Chemoresistance through LIN28A-Mediated ATG12 mRNA Stabilization in Breast Cancer. Pharmacology 12 36382664
2020 WASF3 Knockdown Sensitizes Gastric Cancer Cells to Oxaliplatin by Inhibiting ATG12-Mediated Autophagy. The American journal of the medical sciences 12 32359534
2023 ARL6IP5 Ameliorates α-Synuclein Burden by Inducing Autophagy via Preventing Ubiquitination and Degradation of ATG12. International journal of molecular sciences 11 37445677
2020 Interference of miR-107 with Atg12 is inhibited by HULC to promote metastasis of hepatocellular carcinoma. MedComm 11 34766115
2014 Tougu Xiaotong capsule promotes chondrocyte autophagy by regulating the Atg12/LC3 conjugation systems. International journal of molecular medicine 11 24899049
2025 The Role of WIPI2, ATG16L1 and ATG12-ATG5 in Selective and Nonselective Autophagy. Journal of molecular biology 10 40221132
2024 ATG12-ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage. Autophagy 9 37872727
2019 Erythropoietin helix B surface peptide modulates miR-21/Atg12 axis to alleviates cardiomyocyte hypoxia-reoxygenation injury. American journal of translational research 9 31105848
2023 MiR-3653 blocks autophagy to inhibit epithelial-mesenchymal transition in breast cancer cells by targeting the autophagy-regulatory genes ATG12 and AMBRA1. Chinese medical journal 8 37464439
2021 Long‑chain non‑coding RNA GAS5 promotes cell autophagy by modulating the miR‑181c‑5p/ATG5 and miR‑1192/ATG12 axes. International journal of molecular medicine 8 34608496
2021 miR-378-3p alleviates contusion spinal cord injury by negatively regulating ATG12. International journal of experimental pathology 8 34709686
2008 Crystallization of the Atg12-Atg5 conjugate bound to Atg16 by the free-interface diffusion method. Journal of synchrotron radiation 8 18421155
2025 DNA hypermethylation-induced suppression of ALKBH5 is required for folic acid to alleviate hepatic lipid deposition by enhancing autophagy in an ATG12-dependent manner. The Journal of nutritional biochemistry 7 39993647
2024 LncRNA NR_030777 promotes mitophagy by targeting CDK1-related mitochondrial fission and ATG12 to attenuate paraquat-induced Parkinson's disease. Environmental pollution (Barking, Essex : 1987) 7 38548152
2022 Harmol hydrochloride dihydrate induces autophagy in neuro cells and promotes the degradation of α-Syn by Atg5/Atg12-dependent pathway. Food science & nutrition 7 36514773
2021 Atg12-Interacting Motif Is Crucial for E2-E3 Interaction in Plant Atg8 System. Biological & pharmaceutical bulletin 7 34193767
2021 Toxoplasma gondii profilin and tachyzoites RH strain may manipulate autophagy via downregulating Atg5 and Atg12 and upregulating Atg7. Molecular biology reports 7 34453672
2011 Who put the "A" in Atg12: autophagy or apoptosis? Molecular cell 7 22195958
2019 Grouper Atg12 negatively regulates the antiviral immune response against Singapore grouper iridovirus (SGIV) infection. Fish & shellfish immunology 6 31421242

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