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ATG2B

Autophagy-related protein 2 homolog B · UniProt Q96BY7

Length
2078 aa
Mass
232.8 kDa
Annotated
2026-06-09
28 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATG2B is a component of the core autophagic machinery that promotes autophagosome formation and sustains autophagic flux across multiple cell types (PMID:22350415, PMID:33077697). Its function is gated by opposing post-translational controls: SIRT1-mediated deacetylation activates ATG2B-dependent autophagy and links acetate metabolism and glycolysis to autophagy through an ACSS2/SIRT1/ATG2B axis (PMID:39362518), while the same deacetylation enhances ATG2B binding to the E3 ubiquitin ligase RNF5, which drives its ubiquitin-dependent degradation; the circular RNA circDHX8 antagonizes RNF5 to stabilize ATG2B and promote autophagy (PMID:38866787). ATG2B is additionally repressed at the post-transcriptional level by several miRNAs, including miR-130a and miR-143, whose targeting of the ATG2B 3'-UTR suppresses autophagy and thereby modulates downstream outcomes such as NF-κB-driven inflammation (PMID:29562274), chemosensitivity (PMID:33077697), and cell proliferation (PMID:33611856). Beyond bulk autophagy, ATG2B has a distinct role in hematopoiesis: it cooperates with GSKIP, and germline overexpression of the pair increases hematopoietic progenitor sensitivity to thrombopoietin and predisposes to myeloproliferative neoplasms (PMID:26280900), whereas combined loss of Atg2b and Gskip depletes the hematopoietic stem cell pool through an oxidative-phosphorylation-linked, autophagy-independent mechanism (PMID:34748402).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2009 Low

    Established the first link between ATG2B and human cancer by asking whether ATG2B is genetically altered in tumors with genomic instability.

    Evidence SSCP analysis of a mononucleotide repeat in MSI-H gastric and colorectal tumor samples

    PMID:19197948

    Open questions at the time
    • No functional validation that the frameshift mutations abolish ATG2B activity
    • Does not establish a causal role in tumorigenesis
    • Mechanism of any resulting autophagy deregulation untested
  2. 2012 Medium

    Defined ATG2B as a functional autophagy effector by showing its depletion reduces autophagosome formation, and identified miR-130a as a direct upstream repressor.

    Evidence miR-130a overexpression, ATG2B RNAi, and autophagosome assays in CLL cell lines and primary cells

    PMID:22350415

    Open questions at the time
    • Molecular step of autophagosome formation served by ATG2B not defined
    • No direct 3'-UTR binding shown in this study
    • Partners in the autophagy machinery not identified
  3. 2015 Medium

    Revealed a non-canonical hematopoietic function by showing germline ATG2B/GSKIP overexpression primes progenitors toward myeloid malignancy.

    Evidence iPSC and primary-cell models from families with a 700-kb germline duplication, with TPO-stimulated differentiation assays

    PMID:26280900

    Open questions at the time
    • Whether the effect requires ATG2B autophagic activity unresolved
    • Molecular basis of cooperation with GSKIP unknown
    • Mechanism of enhanced TPO sensitivity not defined
  4. 2016 Low

    Extended miRNA control of ATG2B to innate immunity by showing miR-1303 restrains mycobacteria-induced autophagy via the ATG2B 3'-UTR.

    Evidence Luciferase 3'-UTR reporter and autophagy readout in BCG-infected macrophages with PI3K/NF-κB inhibitors

    PMID:26771516

    Open questions at the time
    • Single-method autophagy readout limits confidence
    • ATG2B protein-level effects of miR-1303 only indirectly shown
    • Physiological relevance to infection control untested
  5. 2018 Medium

    Placed ATG2B-driven autophagy upstream of inflammatory signaling by linking miR-143 repression of ATG2B to reduced IκBα and NF-κB activation.

    Evidence Dual-luciferase 3'-UTR reporter, LC3/IκBα immunoblot, and TEM in intestinal epithelial cells

    PMID:29562274

    Open questions at the time
    • Mechanism connecting ATG2B autophagy to IκBα stability not detailed
    • In vivo relevance to Crohn's disease not directly tested
    • Whether NF-κB effect is autophagy-dependent unconfirmed
  6. 2020 Medium

    Demonstrated ATG2B is rate-limiting for autophagy-mediated chemoresistance by rescuing miR-143 phenotypes through ATG2B/ATG7 co-expression.

    Evidence miR-143 gain/loss, ATG2B+ATG7 rescue, viability and caspase apoptosis assays in AML lines and primary cells

    PMID:33077697

    Open questions at the time
    • Relative contribution of ATG2B vs ATG7 not separated
    • Mechanistic link between autophagy and caspase suppression not defined
    • No structural or interaction data for ATG2B
  7. 2021 Medium

    Showed ATG2B/GSKIP loss depletes the HSC pool through an autophagy-independent, oxidative-phosphorylation-linked mechanism, dissociating ATG2B's hematopoietic role from bulk autophagy.

    Evidence Double-knockout mice with fetal-liver HSC flow cytometry, gene expression analysis, and autophagy flux assays

    PMID:34748402

    Open questions at the time
    • Molecular mechanism of the OXPHOS gene increase unknown
    • How ATG2B and GSKIP act synergistically not defined
    • Whether a residual autophagy function contributes not excluded
  8. 2021 Medium

    Generalized ATG2B as a pro-autophagic, pro-proliferative effector in vascular cells downstream of miR-130a.

    Evidence miR-130a overexpression with ATG2B knockdown/rescue, proliferation and LC3 assays, and a rat arteriosclerosis model

    PMID:33611856

    Open questions at the time
    • Link between autophagy and proliferation control mechanistically unclear
    • ATG2B interactors in VSMCs not identified
    • Direct miR-130a–ATG2B binding in this context not shown
  9. 2024 Medium

    Identified the post-translational stability control of ATG2B by establishing RNF5 as the E3 ligase driving its degradation and circDHX8 as an RNF5-sequestering stabilizer.

    Evidence RNA pulldown/MS, RIP, reciprocal co-IP, ubiquitination immunoblot, and circDHX8 interference in gastric cancer in vitro and in vivo

    PMID:38866787

    Open questions at the time
    • Ubiquitination site(s) on ATG2B not mapped
    • Whether RNF5 ubiquitinates ATG2B directly vs via cofactors unconfirmed
    • Quantitative impact on autophagosome formation not measured
  10. 2024 Medium

    Defined acetylation as a regulatory switch on ATG2B by showing SIRT1 deacetylation activates ATG2B-dependent autophagy and couples it to acetate/glycolytic metabolism.

    Evidence CUT&TAG, co-IP, ACSS2 knockdown, stable-isotope labeling, and Seahorse assays in ovarian cancer models in vitro and in vivo

    PMID:39362518

    Open questions at the time
    • Acetylation sites on ATG2B not mapped
    • How deacetylation mechanistically activates autophagy unclear
    • Interplay between SIRT1 activation and RNF5-mediated degradation not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular function of ATG2B within the autophagosome-formation machinery and the structural basis of its regulation remain undefined.
  • No biochemical/structural characterization of ATG2B's role in membrane dynamics in this corpus
  • Acetylation and ubiquitination sites unmapped
  • How autophagy-dependent and autophagy-independent (HSC/OXPHOS) functions are partitioned is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Pathway
R-HSA-9612973 Autophagy 4
Partners
GSKIPRNF5SIRT1

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Germline overexpression of ATG2B (together with GSKIP) enhances hematopoietic progenitor differentiation, including megakaryocyte differentiation, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during myeloproliferative neoplasm development. Induced pluripotent stem cell models and primary cells from families carrying a 700-kb germline duplication; functional differentiation assays with TPO stimulation Nature genetics Medium 26280900
2021 Loss of both Atg2b and Gskip (but not either alone) in mice causes decreased hematopoietic stem cell (HSC) pool size, increased HSC death, and lethality in utero with anemia; mechanistically, double knockout increased expression of oxidative phosphorylation genes without affecting bulk autophagy, indicating a synergistic non-autophagy role for Atg2b and Gskip in HSC maintenance. Double-knockout mouse model; flow cytometry of HSC populations in fetal liver; gene expression analysis; autophagy flux assays Molecular and cellular biology Medium 34748402
2012 ATG2B is a direct target of miR-130a; miR-130a-mediated downregulation of ATG2B reduces autophagosome formation and inhibits autophagic flux in CLL cells. miRNA overexpression, RNA interference knockdown of ATG2B, autophagosome formation assay in CLL cell lines and primary CLL cells Cancer research Medium 22350415
2018 miR-143 directly targets ATG2B 3'-UTR; miR-143-mediated suppression of ATG2B inhibits autophagy, reduces IκBα levels, and increases inflammatory responses in intestinal epithelial cells, placing ATG2B upstream of NF-κB signaling in Crohn's disease-associated inflammation. 3'-UTR dual-luciferase reporter assay; immunoblot for LC3 and IκBα; transmission electron microscopy for autophagy; constitutive miR-143 expression and ATG2B depletion in intestinal epithelial cells Inflammatory bowel diseases Medium 29562274
2020 miR-143 directly targets ATG2B and ATG7; co-expression of ATG2B and ATG7 rescues miR-143-suppressed autophagy and attenuates miR-143-enhanced cytarabine cytotoxicity via suppression of caspase-dependent apoptosis in AML cells, establishing ATG2B as a critical component of the autophagic machinery regulating chemosensitivity. miR-143 overexpression and knockdown; ATG2B and ATG7 co-expression rescue experiments; cell viability assays; caspase apoptosis assays in AML cell lines and primary AML cells Aging Medium 33077697
2021 miR-130a suppresses VSMC proliferation by targeting ATG2B and inhibiting ATG2B-dependent autophagy; ATG2B overexpression reverses miR-130a-mediated autophagy inhibition and rescues proliferation, placing ATG2B as a pro-autophagic and pro-proliferative effector downstream of miR-130a in vascular smooth muscle cells. miR-130a overexpression; ATG2B knockdown and rescue plasmid co-transfection; CCK-8/cell cycle assays; LC3 Western blot; rat arteriosclerosis model with immunohistochemistry Journal of cellular and molecular medicine Medium 33611856
2016 miR-1303 directly targets ATG2B mRNA, negatively regulating ATG2B protein production and thereby downregulating mycobacteria-induced autophagy in macrophages; miR-1303 production is upregulated during BCG infection and regulated by PI3K and NF-κB signaling. Luciferase reporter assay targeting ATG2B 3'-UTR; miR-1303 overexpression; autophagy measurement in BCG-infected cells; PI3K/NF-κB pathway inhibitors PloS one Low 26771516
2024 The E3 ubiquitin ligase RNF5 mediates ubiquitin-dependent degradation of ATG2B; the circular RNA circDHX8 directly binds RNF5 and inhibits RNF5-mediated degradation, thereby stabilizing ATG2B protein and promoting autophagy and gastric cancer malignancy. Additionally, ATG2B is an acetylated protein subjected to SIRT1-mediated deacetylation, which enhances its binding to RNF5. RNA pulldown, mass spectrometry, RNA immunoprecipitation (RIP), co-immunoprecipitation; Western blotting for ubiquitination; circDHX8 interference in vitro and in vivo Cell death & disease Medium 38866787
2024 SIRT1 mediates deacetylation of ATG2B (and ATG5), and this deacetylation activates autophagy in ovarian cancer cells; the ACSS2/SIRT1/ATG2B axis links acetate metabolism and glycolysis to autophagy regulation. CUT&TAG; co-immunoprecipitation; ACSS2 knockdown; stable-isotope labeling; Seahorse metabolic assays; in vitro and in vivo tumor models Metabolism: clinical and experimental Medium 39362518
2009 ATG2B harbors a mononucleotide repeat susceptible to frameshift mutations in microsatellite instability-high (MSI-H) gastric and colorectal cancers; frameshift mutations were detected in 10 MSI-H cancers, suggesting ATG2B loss-of-function mutations may deregulate autophagy in these tumors. Single-strand conformation polymorphism (SSCP) analysis of mononucleotide repeats in tumor samples The Journal of pathology Low 19197948
2021 ATG2B upregulated in LPS-pretreated BMSC-derived exosomes (L-Exo) attenuates septic liver injury by enhancing mitophagy and inhibiting release of mitochondrial DNA into the cytosol, thereby suppressing macrophage STING signaling. In vivo cecal ligation and puncture sepsis model; in vitro macrophage experiments; exosome ultracentrifugation; mitophagy assays; mtDNA cytosolic release measurement; STING pathway analysis International immunopharmacology Low 36857936

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 miRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells. Cancer research 168 22350415
2015 Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nature genetics 104 26280900
2021 LncRNA-HOTAIR activates autophagy and promotes the imatinib resistance of gastrointestinal stromal tumor cells through a mechanism involving the miR-130a/ATG2B pathway. Cell death & disease 54 33824300
2018 MicroRNA-143 Targets ATG2B to Inhibit Autophagy and Increase Inflammatory Responses in Crohn's Disease. Inflammatory bowel diseases 52 29562274
2020 MicroRNA-375 exacerbates knee osteoarthritis through repressing chondrocyte autophagy by targeting ATG2B. Aging 45 32335541
2022 Autophagy inhibits cancer stemness in triple-negative breast cancer via miR-181a-mediated regulation of ATG5 and/or ATG2B. Molecular oncology 44 35029026
2016 Aberrant methylation of ATG2B, ATG4D, ATG9A and ATG9B CpG island promoter is associated with decreased mRNA expression in sporadic breast carcinoma. Gene 36 27265029
2020 miR-1278 sensitizes nasopharyngeal carcinoma cells to cisplatin and suppresses autophagy via targeting ATG2B. Molecular and cellular probes 27 32407879
2024 Inhibition of ACSS2 triggers glycolysis inhibition and nuclear translocation to activate SIRT1/ATG5/ATG2B deacetylation axis, promoting autophagy and reducing malignancy and chemoresistance in ovarian cancer. Metabolism: clinical and experimental 26 39362518
2020 MicroRNA-143 sensitizes acute myeloid leukemia cells to cytarabine via targeting ATG7- and ATG2B-dependent autophagy. Aging 25 33077697
2016 MiR-1303 Regulates Mycobacteria Induced Autophagy by Targeting Atg2B. PloS one 24 26771516
2023 Ginsenoside Rg1 attenuates the NASH phenotype by regulating the miR-375-3p/ATG2B/PTEN-AKT axis to mediate autophagy and pyroptosis. Lipids in health and disease 20 36759837
2023 ATG2B upregulated in LPS-stimulated BMSCs-derived exosomes attenuates septic liver injury by inhibiting macrophage STING signaling. International immunopharmacology 20 36857936
2020 miR-375 targeting autophagy-related 2B (ATG2B) suppresses autophagy and tumorigenesis in cisplatin-resistant osteosarcoma cells. Neoplasma 19 32726125
2021 Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms. Leukemia 17 34172895
2021 Crocin exerts anti-proliferative and apoptotic effects on cutaneous squamous cell carcinoma via miR-320a/ATG2B. Bioengineered 17 34320900
2024 Human gastric cancer progression and stabilization of ATG2B through RNF5 binding facilitated by autophagy-associated CircDHX8. Cell death & disease 14 38866787
2021 MicroRNA-130a inhibits proliferation of vascular smooth muscle cells by suppressing autophagy via ATG2B. Journal of cellular and molecular medicine 13 33611856
2021 Downregulation of LINC01296 suppresses non-small-cell lung cancer via targeting miR-143-3p/ATG2B. Acta biochimica et biophysica Sinica 13 34695177
2015 ATG2B and GSKIP: 2 new genes predisposing to myeloid malignancies. Molecular & cellular oncology 11 27308616
2020 MiR-143-3p targets ATG2B to inhibit autophagy and promote endothelial progenitor cells tube formation in deep vein thrombosis. Tissue & cell 10 33130456
2023 Ame-miR-980-3p participates in autophagy-mediated midgut remodelling in Apis mellifera via targeting Atg2B. Insect molecular biology 5 37658706
2021 Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size. Molecular and cellular biology 5 34748402
2023 Effect of melatonin on ATG2B-mediated autophagy regulation in sheep granulosa cells with different FecB genotypes. Journal of pineal research 4 37226314
2016 [Expressions and Clinical Significance of Autophagy-related Genes ATG2B, ATG4D, ATG9B in Breast Carcinoma]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 4 27263291
2025 Ghrelin improves small intestinal barrier damage in sepsis by promoting miR-143/ATG2B-mediated autophagy. PloS one 0 40773487
2020 Polymorphism in autophagy gene ATG2B is not associated with bladder cancer recurrence after intravesical Bacillus Calmette-Guerin (BCG) immunotherapy in Asian patients. Urologic oncology 0 33250346

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