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AMBRA1

Activating molecule in BECN1-regulated autophagy protein 1 · UniProt Q9C0C7

Length
1298 aa
Mass
142.5 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AMBRA1 is an intrinsically disordered scaffold protein that integrates autophagy initiation, cell cycle control, mitophagy, and inflammatory signaling through its dual roles as a BECLIN1-VPS34 complex regulator and as the substrate receptor of the CRL4(DDB1-CUL4) E3 ubiquitin ligase. In resting cells, AMBRA1 tethers the BECLIN1-VPS34 autophagy initiation complex to the dynein motor via DLC1; upon starvation, ULK1 phosphorylates AMBRA1, releasing the complex for ER-localized autophagosome nucleation, while AMBRA1 simultaneously recruits TRAF6 to K63-ubiquitylate and stabilize ULK1, forming a positive feedback loop (PMID:20921139, PMID:23524951, PMID:25499913). As the substrate receptor of CRL4^AMBRA1, it ubiquitylates and degrades all three D-type cyclins to enforce the G1-S checkpoint—loss of AMBRA1 causes replication stress and genomic instability—and also targets Elongin C to antagonize CRL5 activity, and mediates nonproteolytic K63-ubiquitylation of Smad4 to potentiate TGFβ signaling (PMID:33854235, PMID:33854232, PMID:30166453, PMID:34362797). AMBRA1 further promotes PINK1/PARKIN-dependent and HUWE1-dependent mitophagy by stabilizing PINK1 at the outer mitochondrial membrane and by IKKα-mediated phosphorylation (S1014) that enhances LC3/GABARAP binding, and it modulates NF-κB signaling in an autophagy-independent manner by competing with PP4R1 for IKK binding (PMID:34798798, PMID:30217973, PMID:38424148, PMID:21753002).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2007 High

    The foundational discovery that AMBRA1 is a positive regulator of BECLIN1-dependent autophagy, and that its loss causes neural tube defects with impaired autophagy and excessive apoptosis, established AMBRA1 as a core autophagy gene with essential developmental functions.

    Evidence Mouse knockout/hypomorphic model, RNAi, and overexpression assays in Nature

    PMID:17589504

    Open questions at the time
    • No binding interface or mechanism of action on BECLIN1 resolved
    • Molecular basis for the proliferation/apoptosis imbalance not identified
  2. 2010 High

    Determining that AMBRA1 physically tethers the BECLIN1-VPS34 complex to dynein via DLC1, and that ULK1 phosphorylation releases this complex for ER relocalization, resolved how autophagosome nucleation is spatially controlled and placed ULK1 upstream of AMBRA1.

    Evidence Reciprocal Co-IP, DLC1-binding site mutagenesis, ULK1 kinase assay, live-cell imaging

    PMID:20921139

    Open questions at the time
    • ULK1 phosphorylation sites on AMBRA1 not mapped
    • Mechanism of ER membrane recruitment after dynein release unknown
  3. 2011 High

    Showing that AMBRA1 binds preferentially to mitochondrial BCL-2 and competes with BCL-2 for BECLIN1 binding linked AMBRA1 to the BCL-2/BECLIN1 regulatory node, while the discovery of Parkin-dependent AMBRA1 recruitment to depolarized mitochondria established AMBRA1 as a mitophagy effector that activates class III PI3K locally.

    Evidence Subcellular fractionation with Co-IP (BCL-2 study); TAP-MS from HEK293/SH-SY5Y/mouse brain with reciprocal Co-IP and AMBRA1 siRNA mitophagy readout (Parkin study)

    PMID:21358617 PMID:21753002

    Open questions at the time
    • BCL-2 binding site on AMBRA1 not mapped
    • Direct mechanism by which AMBRA1 activates VPS34 at mitochondria unresolved
  4. 2012 High

    Demonstrating caspase cleavage at D482 and calpain-mediated degradation of AMBRA1 during apoptosis revealed that AMBRA1 destruction terminates pro-survival autophagy; this was extended in 2016 by showing the C-terminal cleavage fragment contains a BH3-like domain that directly inhibits BCL-2 to amplify apoptosis.

    Evidence In vitro cleavage assays, caspase non-cleavable mutant, BH3 domain mutagenesis with apoptosis readouts

    PMID:22441670 PMID:27123694

    Open questions at the time
    • In vivo relevance of the BH3-fragment proapoptotic loop not tested
    • Calpain cleavage sites not precisely mapped
  5. 2013 High

    Establishing that mTOR phosphorylates AMBRA1 to suppress autophagy, and that upon mTOR inhibition AMBRA1 recruits TRAF6 to K63-ubiquitylate and stabilize ULK1, defined a bistable positive feedback loop (ULK1→AMBRA1→TRAF6→ULK1) governing the autophagy on/off switch.

    Evidence Co-IP, K63-linkage-specific ubiquitylation assays, mTOR inhibition/activation, ULK1 kinase assays

    PMID:23524951

    Open questions at the time
    • mTOR phosphorylation sites on AMBRA1 not mapped
    • Whether TRAF6 is the sole E3 for ULK1 K63-ubiquitylation not resolved
  6. 2014 High

    Multiple 2014 discoveries expanded AMBRA1 beyond autophagy: CUL4 was shown to degrade AMBRA1 basally while AMBRA1 reciprocally inhibits CUL5 to stabilize DEPTOR; RNF2/WASH promotes K48-ubiquitylation of AMBRA1 at K45; and AMBRA1 recruits PP2A to dephosphorylate c-Myc, promoting its degradation and revealing AMBRA1 as a haploinsufficient tumor suppressor.

    Evidence Co-IP and ubiquitylation assays (CUL4/CUL5 and RNF2 studies); PP2A phosphatase assay, c-Myc stability assays, AMBRA1 KO tumor models (c-Myc study)

    PMID:24980959 PMID:25438055 PMID:25499913

    Open questions at the time
    • CUL4 binding site on AMBRA1 not structurally resolved at this stage
    • CUL5 inhibition mechanism not fully dissected
    • PP2A subunit specificity for AMBRA1-mediated c-Myc dephosphorylation undefined
  7. 2017 High

    AMBRA1 was found to regulate spatial distribution of active Src kinase between focal adhesions and autophagic structures, controlling cancer cell invasion; separately, AMBRA1 was shown to bind phospho-S129 α-synuclein with ninefold higher affinity, with AMBRA1 loss causing α-synuclein aggregation in neurons.

    Evidence Interaction proteomics with Co-IP and live-cell phospho-Src imaging (Src study); Co-IP with binding affinity quantification and siRNA in primary neurons (α-synuclein study)

    PMID:27875637 PMID:28362576

    Open questions at the time
    • Direct Src phosphorylation sites relevant to AMBRA1 not mapped
    • Whether AMBRA1-α-synuclein binding is direct or complex-mediated not resolved
    • In vivo neurodegeneration relevance not tested
  8. 2018 High

    Three discoveries in 2018 deepened the CRL4 and mitophagy axes: IKKα phosphorylation of AMBRA1 at S1014 enhances LC3/GABARAP binding for HUWE1-dependent mitophagy; MCL1 degradation by GSK-3β/HUWE1 licenses AMBRA1-dependent mitophagy; CRL4^AMBRA1 targets Elongin C for degradation to antagonize CRL5 complexes; and AMBRA1/PP2A stabilizes FOXO3 to drive FOXP3 transcription and Treg differentiation.

    Evidence In vitro kinase/phosphomimetic mutants with mitophagy readouts; proteomics-validated ubiquitination of Elongin C; PP2A activity assay with in vivo Treg models

    PMID:30166453 PMID:30217973 PMID:30513302 PMID:31434979

    Open questions at the time
    • Full phosphorylation landscape of AMBRA1 during mitophagy not mapped
    • Whether CRL4-AMBRA1 targets Elongin C constitutively or conditionally unclear
    • PP2A holoenzyme composition in Treg context not specified
  9. 2019 High

    AMBRA1 was shown to scaffold TRIM32 to ULK1 in muscle cells, with TRIM32 activating ULK1 via K63-polyubiquitin chains; muscular dystrophy 2H mutations disrupt this interaction, linking AMBRA1 to disease-relevant autophagy regulation in skeletal muscle.

    Evidence In vitro ULK1 kinase assay, TRIM32 disease mutant analysis, autophagy flux in muscle cells

    PMID:31234693

    Open questions at the time
    • Direct binding interface between AMBRA1 and TRIM32 not mapped
    • Whether AMBRA1 loss alone recapitulates the TRIM32 muscular phenotype untested
  10. 2020 High

    FRET-validated interaction of AMBRA1 with ERLIN1 at mitochondria-associated membranes (MAMs) showed that ganglioside GD3- and MFN2-dependent lipid raft-like microdomains provide a specific membrane platform for AMBRA1-dependent autophagosome formation.

    Evidence Co-IP, FRET analysis at MAMs, siRNA knockdown of ERLIN1/ST8SIA1/MFN2 with autophagy flux readout

    PMID:33034545

    Open questions at the time
    • Whether ERLIN1 binding is direct or via an intermediate not resolved
    • Lipid composition requirements beyond GD3 not characterized
  11. 2021 High

    A breakthrough year established AMBRA1 as the D-type cyclin-degrading substrate receptor of CRL4: three simultaneous Nature papers showed CRL4^AMBRA1 ubiquitylates cyclin D1/D2/D3, cancer hotspot mutations escape this degradation, and AMBRA1 loss causes replication stress with CHK1 synthetic lethality; concurrently, AMBRA1 was shown to stabilize PINK1 at the OMM by counteracting ATAD3A-mediated import, to K63-ubiquitylate Smad4 for TGFβ signaling, and to stabilize MAVS for antiviral apoptosis.

    Evidence Genome-wide CRISPR screens, reconstituted ubiquitylation, in vivo mouse models (cyclin D papers); Co-IP at OMM fractions with epistasis analysis (PINK1); in vitro K63-ubiquitylation and metastasis models (Smad4); Co-IP and MAVS stability assays (MAVS)

    PMID:33854232 PMID:33854235 PMID:33854239 PMID:34362797 PMID:34798798 PMID:34859815

    Open questions at the time
    • Structural basis of cyclin D recognition by AMBRA1 not yet resolved at this stage
    • Whether Smad4 K63-ubiquitylation occurs genome-wide or at specific loci undefined
    • MAVS stabilization mechanism awaits independent confirmation
  12. 2022 High

    Muscle-specific AMBRA1 conditional knockout demonstrated in vivo that AMBRA1 is required for mitophagic flux in skeletal muscle, with its loss causing mitochondrial swelling, impaired DRP1/Parkin recruitment, and reduced oxidative fiber proportion.

    Evidence Conditional KO (Ambra1fl/fl:Mlc1f-Cre), electron microscopy, respiratory complex assay, AMBRA1 overexpression rescue

    PMID:35593053

    Open questions at the time
    • Whether AMBRA1 acts through PINK1/PARKIN or HUWE1 pathway in muscle not resolved
    • Contribution of autophagy-independent AMBRA1 functions to the muscle phenotype unclear
  13. 2023 High

    The 3.08 Å cryo-EM structure of AMBRA1-DDB1 revealed that AMBRA1's N-terminal helix-loop-helix and WD40 domain engage DDB1's double-propeller, providing the first structural basis for CRL4^AMBRA1 assembly and cyclin D ubiquitylation; separately, CDK1/PLK1-dependent mitotic phosphorylation of AMBRA1 was shown to regulate NUMA1 localization and spindle orientation.

    Evidence Cryo-EM at 3.08 Å with HDX-MS and DDB1-binding mutants validated by ubiquitylation and cell cycle assays; in vitro CDK1/PLK1 kinase assays with phosphomutants and live-cell spindle imaging

    PMID:37584777 PMID:37993427

    Open questions at the time
    • No structure with a cyclin D substrate bound
    • Mitotic phosphosite identities and their individual contributions to spindle orientation not fully dissected
  14. 2024 High

    New regulatory inputs were defined: BAG2, a ULK1 complex effector, sequesters AMBRA1 until ULK1 phosphorylates BAG2 at S31 to release AMBRA1 for ER recruitment; independently, AMBRA1 was shown to sustain NF-κB signaling in an autophagy-independent manner by competitively blocking PP4R1/PP4c dephosphorylation of IKK, with IKKα phosphorylating AMBRA1 at S1043 to prevent its CUL4A-mediated degradation.

    Evidence AP-MS/proximity labeling with Co-IP and phosphomimetic BAG2 mutants (BAG2 study); in vitro phosphatase competition assay, AMBRA1 KO colitis model, S1043 phosphomimetic with ubiquitylation assay (NF-κB study)

    PMID:38424148 PMID:39207901

    Open questions at the time
    • BAG2-AMBRA1 binding interface not structurally resolved
    • Whether BAG2-dependent regulation is universal or cell-type-specific unclear
    • Full IKK substrate landscape of AMBRA1 phosphorylation sites not mapped
  15. 2025 High

    USP7 was identified as the deubiquitinase stabilizing AMBRA1 at K83/K86 under oxidative stress; stabilized AMBRA1 suppresses NRF2 by competitively displacing DUB3 from NRF2's N-terminus, linking AMBRA1 to redox homeostasis control.

    Evidence In vitro deubiquitination assay, K83/K86 site mapping, domain mutagenesis (F1 domain), NRF2 stability assays, USP7 inhibitor in vivo

    PMID:39887666

    Open questions at the time
    • Whether USP7-AMBRA1-NRF2 axis operates during autophagy or independently unclear
    • In vivo relevance of NRF2 suppression by AMBRA1 in specific tissues not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions remain: no full-length AMBRA1 structure exists; the structural basis for cyclin D and other substrate recognition by CRL4^AMBRA1 is unresolved; the relative contributions of AMBRA1's autophagy-dependent versus autophagy-independent functions in tumorigenesis and inflammation need systematic dissection; and the complete phosphorylation code governing AMBRA1's switch between its multiple effector modes is unknown.
  • No full-length AMBRA1 structure
  • Cyclin D substrate-bound CRL4 structure lacking
  • Systematic separation of autophagy-dependent vs independent functions in vivo needed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060090 molecular adaptor activity 5 GO:0038024 cargo receptor activity 4
Localization
GO:0005739 mitochondrion 5 GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 3
Pathway
R-HSA-9612973 Autophagy 8 R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3
Partners
BECN1DDB1DLC1PINK1PP2APRKNTRAF6ULK1
Complex memberships
BECLIN1-VPS34 autophagy initiation complexCRL4(DDB1-CUL4A)ULK1 complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 AMBRA1 was identified as a positive regulator of BECLIN1-dependent autophagy; it contains a WD40 domain and its loss in mouse embryos impairs autophagy, causes accumulation of ubiquitinated proteins, and leads to severe neural tube defects with unbalanced cell proliferation and excessive apoptosis. RNA interference in vitro, overexpression assays, and mouse knockout/hypomorphic model with phenotypic readout Nature High 17589504
2010 AMBRA1 tethers the BECLIN1-VPS34 core complex to the dynein motor through direct interaction with dynein light chains 1/2 (DLC1/2); upon autophagy induction, ULK1 phosphorylates AMBRA1, releasing the complex from dynein and allowing its relocalization to the ER where autophagosome nucleation occurs. Co-immunoprecipitation, live-cell imaging, ULK1 kinase assay, dominant-negative DLC1 experiments, AMBRA1 DLC1-binding site mutagenesis The Journal of cell biology High 20921139
2011 AMBRA1 binds preferentially to the mitochondrial pool of BCL-2; upon autophagy induction this interaction is disrupted, releasing AMBRA1 to promote BECLIN1 activity; AMBRA1 can compete with both mitochondrial and ER-resident BCL-2 for BECLIN1 binding. Co-immunoprecipitation, subcellular fractionation, overexpression and knockdown assays The EMBO journal High 21358617
2011 Parkin interacts with AMBRA1 and this interaction increases strongly during prolonged mitochondrial depolarization; AMBRA1 is recruited in a Parkin-dependent manner to perinuclear clusters of depolarized mitochondria and activates PI3K (class III) locally to promote mitophagy; AMBRA1 is not required for Parkin translocation but is critical for subsequent mitochondrial clearance. Tandem affinity purification/mass spectrometry, reciprocal co-immunoprecipitation from HEK293, SH-SY5Y, and mouse brain; AMBRA1 siRNA knockdown with mitophagy readout The Journal of neuroscience High 21753002
2012 During apoptosis, AMBRA1 is cleaved by caspases at D482 and further degraded by calpains; a caspase non-cleavable AMBRA1 mutant prolongs autophagy and counteracts cell death; AMBRA1 downregulation sensitizes cells to apoptotic stimuli. In vitro cleavage assays, caspase/calpain inhibitor experiments, caspase non-cleavable mutant, siRNA knockdown with apoptosis readout Cell death and differentiation High 22441670
2013 Under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation; upon autophagy induction AMBRA1 is dephosphorylated and then interacts with the E3 ligase TRAF6 to promote K63-linked ubiquitylation and stabilization of ULK1, forming a positive feedback loop with ULK1-mediated AMBRA1 phosphorylation. Co-immunoprecipitation, ubiquitylation assays (K63 linkage-specific), phosphorylation assays, mTOR inhibition/activation experiments, ULK1 kinase assays Nature cell biology High 23524951
2014 Cullin-4 (CRL4) binds AMBRA1 under basal conditions to limit its abundance via degradation; ULK1-dependent phosphorylation upon autophagy induction causes Cullin-4 to release AMBRA1; the re-established Cullin-4/AMBRA1 interaction terminates autophagy by degrading AMBRA1. Upon Cullin-4 dissociation, AMBRA1 binds and inhibits Cullin-5, stabilizing the mTOR inhibitor DEPTOR to create a positive feedback loop for autophagy onset. Co-immunoprecipitation, ubiquitylation assays, siRNA knockdown, autophagy flux assays Developmental cell High 25499913
2014 AMBRA1 promotes c-Myc dephosphorylation and degradation by directly facilitating the interaction between c-Myc and the phosphatase PP2A; when mTOR is inhibited, AMBRA1 enhances PP2A activity toward c-Myc, reducing cell division rate; loss of AMBRA1 increases tumorigenesis, identifying AMBRA1 as a haploinsufficient tumor suppressor. Co-immunoprecipitation, PP2A phosphatase assay, c-Myc stability assays, AMBRA1 KO/KD with proliferation and tumor growth readouts Nature cell biology High 25438055
2014 RNF2 associates with AMBRA1 and acts as an E3 ligase to ubiquitinate AMBRA1 via K48-linked chains at lysine 45, promoting its proteasomal degradation; WASH recruits RNF2 to AMBRA1 to mediate this degradation and thereby downregulate autophagy. Co-immunoprecipitation, in vitro ubiquitination assay, ubiquitin linkage determination, RNF2 knockdown/overexpression with autophagy flux readout Cell research High 24980959
2016 The C-terminal part of AMBRA1, generated by caspase cleavage during apoptosis, contains a BH3-like domain that directly binds and inhibits the antiapoptotic factor BCL2, creating a proapoptotic positive feedback loop. Co-immunoprecipitation, caspase cleavage assays, BH3 domain mutagenesis, apoptosis assays Autophagy High 27123694
2017 AMBRA1 regulates the spatial activity of Src kinase; it binds both FAK and Src in cancer cells and controls targeting of active phospho-Src away from focal adhesions into autophagic structures. When FAK is present, AMBRA1 is recruited to focal adhesions promoting direction-sensing invasion; trafficking partners Dynactin 1 and IFITM3 were identified as AMBRA1 binding partners by interaction proteomics. Co-immunoprecipitation, interaction proteomics, live-cell imaging of phospho-Src localization, invasion assays, FAK/AMBRA1 mutant analysis eLife High 28362576
2018 The E3 ubiquitin ligase HUWE1 is required for AMBRA1-mediated mitophagy independently of PINK1/PARKIN; IKKα phosphorylates AMBRA1 at serine 1014, promoting structural changes in AMBRA1 that increase its interaction with LC3/GABARAP proteins and mitophagic activity. Co-immunoprecipitation, in vitro kinase assay, phosphomimetic/phosphodeficient mutants, HUWE1 and IKKα knockdown/KO with mitophagy readout (mitochondrial markers, LC3 co-localization) Nature communications High 30217973
2018 AMBRA1 promotes Treg differentiation by interacting with the phosphatase PP2A to stabilize the transcriptional activator FOXO3, which in turn triggers FOXP3 transcription; this pathway was validated in mouse models of tumor growth and multiple sclerosis. Co-immunoprecipitation, PP2A activity assay, FOXO3/FOXP3 reporter assays, AMBRA1 KD with Treg differentiation readout in vivo Developmental cell High 30513302
2018 HUWE1-mediated regulation of MCL1 stability controls AMBRA1-mediated mitophagy: MCL1 overexpression inhibits HUWE1 recruitment to mitochondria; GSK-3β phosphorylates MCL1 at S159 during AMBRA1-mediated mitophagy, triggering HUWE1-dependent MCL1 degradation and enabling mitophagy. Co-immunoprecipitation, mitophagy flux assay, GSK-3β inhibition, phosphomimetic MCL1 mutants, HUWE1 and MCL1 overexpression/knockdown Cell death and differentiation High 31434979
2019 The E3 ubiquitin ligase TRIM32 activates ULK1 kinase activity in muscle cells through unanchored K63-linked polyubiquitin chains; AMBRA1 acts as a scaffold that conveys TRIM32 to ULK1; muscular dystrophy 2H mutations in TRIM32 disrupt its ability to bind ULK1 and induce autophagy. Co-immunoprecipitation, in vitro ULK1 kinase assay, ubiquitin chain type determination, TRIM32 disease mutant analysis, autophagy flux assay in muscle cells Autophagy High 31234693
2020 AMBRA1 interacts with ERLIN1 at MAM (mitochondria-associated membrane) raft-like microdomains; this interaction is essential for autophagosome formation upon nutrient starvation and depends on ganglioside GD3 and MFN2 integrity. Co-immunoprecipitation, FRET analysis, subcellular fractionation to MAMs, siRNA knockdown of ERLIN1/ST8SIA1/MFN2 with autophagy flux readout Autophagy High 33034545
2021 AMBRA1 functions as the substrate receptor for the CRL4 (cullin 4) E3 ubiquitin ligase complex (CRL4AMBRA1/CRL4DCAF3) that targets all three D-type cyclins (cyclin D1, D2, D3) for ubiquitylation and proteasomal degradation; cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and stabilize them. Biochemical ubiquitylation assays, genetic KO in somatic cells and mice, genome-wide CRISPR screen, Co-immunoprecipitation, CDK4/6 inhibitor treatment, in vivo mouse models Nature High 33854232 33854235 33854239
2021 AMBRA1 regulates G1-to-S transition and replication-phase entry by controlling D-type cyclin abundance through both proteasomal degradation and MYC/MYCN-mediated transcription; AMBRA1 loss causes replication stress and genomic instability; CHK1 kinase is a synthetic lethal target in AMBRA1-deficient tumors. Cell cycle analysis, cyclin D protein stability assays, DNA damage markers, AMBRA1 KO mouse models, CHK1 inhibitor sensitivity assays Nature High 33854232
2021 AMBRA1 is recruited to the outer mitochondrial membrane (OMM) upon mitochondrial depolarization where it interacts with PINK1 and ATAD3A; AMBRA1 promotes PINK1 stability by counteracting ATAD3A-mediated import and LONP1-dependent degradation of PINK1, thereby facilitating PINK1-PARKIN mitophagy. Co-immunoprecipitation at OMM fractions, AMBRA1/ATAD3A siRNA knockdown, PINK1 stability assays, mitophagy flux (phospho-ubiquitin, PARKIN recruitment) Autophagy High 34798798
2021 AMBRA1 acts as a substrate receptor for the CRL4 complex to mediate nonproteolytic K63-linked polyubiquitylation of Smad4, enhancing its transcriptional activity and TGFβ signaling, thereby promoting TGFβ-induced EMT, migration, and invasion of breast cancer cells. Co-immunoprecipitation, in vitro ubiquitination assay (K63 linkage determination), Smad4 transcriptional reporter assay, AMBRA1 KD with EMT/invasion readouts, mouse breast cancer metastasis model Cancer research High 34362797
2021 HPV E7 protein interacts with AMBRA1, competes with its binding to BECLIN1, and triggers calpain-dependent AMBRA1 degradation, thereby reducing autophagy activity in HPV-positive oropharyngeal squamous cell carcinoma cells. Co-immunoprecipitation, calpain inhibitor experiments, AMBRA1 and BECLIN1 binding competition assays, autophagy flux assays in HPV+ vs HPV- cells Autophagy High 33172332
2021 AMBRA1 suppresses SOCS3 to maintain STAT3 activation in medulloblastoma; this c-MYC/AMBRA1/STAT3 axis regulates stem cell potential, growth, and migration of Group 3 medulloblastoma. AMBRA1 knockdown in MB stem cells, STAT3 reporter assays, SOCS3 rescue experiments, sphere-forming and invasion assays, autophagy inhibition Acta neuropathologica Medium 34302498
2022 Muscle-specific AMBRA1 knockout in mice leads to impaired mitophagic flux, accumulation of TOMM20, swollen mitochondria, decreased DRP1 and Parkin recruitment to mitochondria, lysosomal accumulation, and reduced oxidative fiber proportion; AMBRA1 overexpression in wild-type muscle is sufficient to enhance mitochondrial clearance. Muscle-specific conditional KO (Ambra1fl/fl:Mlc1f-Cre), AMBRA1 overexpression in vivo, mitochondrial fractionation, electron microscopy, respiratory complex activity assay Journal of cachexia, sarcopenia and muscle High 35593053
2023 Cryo-EM structure of AMBRA1 in complex with DDB1 at 3.08 Å resolution reveals that AMBRA1's N-terminal helix-loop-helix motif and WD40 domain associate with the double-propeller fold of DDB1; DDB1-binding-defective AMBRA1 mutants prevent ubiquitination of cyclin D1 in vitro and increase cell cycle progression. Cryo-EM structure determination, hydrogen-deuterium exchange mass spectrometry (HDX-MS), DDB1-binding mutants, in vitro ubiquitination assay, cell cycle analysis Nature communications High 37993427
2023 AMBRA1 is phosphorylated during mitosis on multiple sites by CDK1 and PLK1; this phosphorylation is required for proper mitotic spindle orientation through regulation of NUMA1 localization and dynamics. In vitro CDK1/PLK1 kinase assays, phosphomimetic/phosphodeficient AMBRA1 mutants, live-cell imaging of spindle orientation, NUMA1 localization analysis, AMBRA1 KD Cellular and molecular life sciences High 37584777
2024 The ULK1 complex effector BAG2 regulates AMBRA1 subcellular localization: in growth conditions, unphosphorylated BAG2 sequesters AMBRA1, attenuating autophagy; upon starvation, ULK1 phosphorylates BAG2 on Ser31, releasing AMBRA1 to be recruited to the ER membrane to promote autophagy. Affinity purification/proximity labeling mass spectrometry, Co-immunoprecipitation, phosphomimetic BAG2 mutants, AMBRA1 localization imaging, autophagy flux assays Cell reports High 39207901
2024 AMBRA1 promotes intestinal inflammation in an autophagy-independent manner by competing with PP4R1/PP4c to bind IKK, thereby antagonizing IKK dephosphorylation and sustaining NF-κB pathway activation; IKKα phosphorylates AMBRA1 at S1043 to stabilize it by impairing its CUL4A-mediated K48-linked ubiquitination. Co-immunoprecipitation, in vitro phosphatase competition assay, AMBRA1 KO mouse colitis model, phosphomimetic S1043 mutant, ubiquitination assays Cell death and differentiation High 38424148
2025 USP7 deubiquitinates AMBRA1 at K83 and K86 in response to H2O2, stabilizing AMBRA1; AMBRA1 in turn suppresses NRF2 by competing with DUB3 for binding to the N-terminal domain of NRF2 through its F1 domain, thereby antagonizing DUB3-mediated NRF2 deubiquitination and promoting NRF2 degradation. Co-immunoprecipitation, in vitro deubiquitination assay, ubiquitination site mapping (K83/K86), NRF2 stability assays, AMBRA1 domain mapping, USP7 inhibitor in vivo Advanced science High 39887666
2018 CRL4AMBRA1 ubiquitin ligase targets Elongin C (ELOC), the essential adapter of CRL5 complexes, for polyubiquitination and degradation, thereby disrupting CRL5 assembly and attenuating CRL5SOCS3 and CRL5VIF activities; AMBRA1 depletion leads to hyperactivation of both CRL5 complexes and altered IL-6/STAT3 signaling and HIV-1 infectivity. Proteomics, co-immunoprecipitation, in vitro ubiquitination assay, AMBRA1 KD with CRL5 activity and STAT3 signaling readouts The EMBO journal High 30166453
2017 AMBRA1 interacts with α-synuclein, showing approximately ninefold stronger affinity for α-synuclein phosphorylated at serine 129 compared to non-phosphorylated α-synuclein; AMBRA1 silencing causes α-synuclein aggregation in primary neurons, and AMBRA1 overexpression reduces abnormal α-synuclein levels. Co-immunoprecipitation with binding affinity measurements, AMBRA1 siRNA knockdown in primary neurons, AMBRA1 overexpression, bafilomycin autophagy inhibition comparison Brain pathology Medium 27875637
2021 AMBRA1 promotes dsRNA- and virus-induced apoptosis by interacting with and stabilizing MAVS at the mitochondria, preventing its proteasomal degradation; this effect requires caspase-8 and mitochondrial MAVS localization. Co-immunoprecipitation, MAVS stability assays with/without AMBRA1 KO, proteasome inhibitor experiments, caspase-8 inhibition, apoptosis assays Journal of cell science Medium 34859815

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Ambra1 regulates autophagy and development of the nervous system. Nature 834 17589504
2013 mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nature cell biology 642 23524951
2010 The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. The Journal of cell biology 395 20921139
2011 Parkin interacts with Ambra1 to induce mitophagy. The Journal of neuroscience : the official journal of the Society for Neuroscience 230 21753002
2018 HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα. Nature communications 227 30217973
2011 Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. The EMBO journal 205 21358617
2014 AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nature cell biology 191 25438055
2012 Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. Autophagy 144 22240590
2021 CRL4AMBRA1 is a master regulator of D-type cyclins. Nature 131 33854235
2021 The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D. Nature 130 33854239
2014 AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy dynamics. Developmental cell 127 25499913
2021 AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity. Nature 119 33854232
2012 Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response. Cell death and differentiation 116 22441670
2014 The autophagy regulators Ambra1 and Beclin 1 are required for adult neurogenesis in the brain subventricular zone. Cell death & disease 105 25188513
2015 Ambra1 at a glance. Journal of cell science 88 26034061
2012 Ambra1 at the crossroad between autophagy and cell death. Oncogene 86 23069654
2014 RNF2 is recruited by WASH to ubiquitinate AMBRA1 leading to downregulation of autophagy. Cell research 84 24980959
2014 Heterozygous ambra1 deficiency in mice: a genetic trait with autism-like behavior restricted to the female gender. Frontiers in behavioral neuroscience 80 24904333
2020 Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs. Autophagy 69 33034545
2020 miR-103a-3p regulates mitophagy in Parkinson's disease through Parkin/Ambra1 signaling. Pharmacological research 67 32942015
2021 AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability. Autophagy 66 34798798
2019 HUWE1 controls MCL1 stability to unleash AMBRA1-induced mitophagy. Cell death and differentiation 65 31434979
2018 AMBRA1-Mediated Mitophagy Counteracts Oxidative Stress and Apoptosis Induced by Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells. Frontiers in cellular neuroscience 65 29755319
2016 Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. Nature genetics 55 27723758
2021 Loss of Ambra1 promotes melanoma growth and invasion. Nature communications 54 33953176
2011 Unleashing the Ambra1-Beclin 1 complex from dynein chains: Ulk1 sets Ambra1 free to induce autophagy. Autophagy 48 21079415
2018 AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis. Developmental cell 44 30513302
2013 Ambra1 knockdown in zebrafish leads to incomplete development due to severe defects in organogenesis. Autophagy 42 23348054
2017 MIR7-3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1. Autophagy 41 28059583
2017 Sexual dimorphism of AMBRA1-related autistic features in human and mouse. Translational psychiatry 40 28994820
2014 Ambra1 is an essential regulator of autophagy and apoptosis in SW620 cells: pro-survival role of Ambra1. PloS one 40 24587252
2013 Expression of Ambra1 in mouse brain during physiological and Alzheimer type aging. Neurobiology of aging 40 23910655
2020 HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1. Autophagy 37 33172332
2017 Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks. eLife 37 28362576
2021 Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling. Acta neuropathologica 34 34302498
2018 Effects of caloric restriction on neuropathic pain, peripheral nerve degeneration and inflammation in normometabolic and autophagy defective prediabetic Ambra1 mice. PloS one 34 30532260
2017 AMBRA1, a novel α-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy. Brain pathology (Zurich, Switzerland) 34 27875637
2016 Ambra1 in autophagy and apoptosis: Implications for cell survival and chemotherapy resistance. Oncology letters 34 27347152
2015 Connecting autophagy: AMBRA1 and its network of regulation. Molecular & cellular oncology 34 27308402
2011 Ambra1: a Parkin-binding protein involved in mitophagy. Autophagy 34 21921694
2024 Role of AMBRA1 in mitophagy regulation: emerging evidence in aging-related diseases. Autophagy 33 39113560
2019 Ambra1 induces autophagy and desensitizes human prostate cancer cells to cisplatin. Bioscience reports 32 29101240
2018 Ambra1 modulates the sensitivity of breast cancer cells to epirubicin by regulating autophagy via ATG12. Cancer science 32 30027574
2015 AMBRA1 and BECLIN 1 interplay in the crosstalk between autophagy and cell proliferation. Cell cycle (Georgetown, Tex.) 31 25803737
2016 Prosurvival AMBRA1 turns into a proapoptotic BH3-like protein during mitochondrial apoptosis. Autophagy 30 27123694
2022 Ambra1 deficiency impairs mitophagy in skeletal muscle. Journal of cachexia, sarcopenia and muscle 29 35593053
2021 Nuclear factor I-C disrupts cellular homeostasis between autophagy and apoptosis via miR-200b-Ambra1 in neural tube defects. Cell death & disease 27 34930914
2019 A TRIM32-AMBRA1-ULK1 complex initiates the autophagy response in atrophic muscle cells. Autophagy 27 31234693
2018 Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders. Molecular neurobiology 27 29488136
2022 Ambra1 regulates apoptosis and chemosensitivity in breast cancer cells through the Akt-FoxO1-Bim pathway. Apoptosis : an international journal on programmed cell death 24 35257265
2020 Rare mutations in the autophagy-regulating gene AMBRA1 contribute to human neural tube defects. Human mutation 23 32333458
2015 AMBRA1 and SQSTM1 expression pattern in prostate cancer. Apoptosis : an international journal on programmed cell death 23 26423274
2021 Deletion of the E3 ubiquitin ligase, Parkin, exacerbates chronic alcohol intake-induced cardiomyopathy through an Ambra1-dependent mechanism. British journal of pharmacology 22 33300167
2022 AMBRA1 and its role as a target for anticancer therapy. Frontiers in oncology 20 36237336
2021 AMBRA1 Promotes TGFβ Signaling via Nonproteolytic Polyubiquitylation of Smad4. Cancer research 19 34362797
2019 Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria. Theoretical biology & medical modelling 19 31665034
2016 shRNA-mediated AMBRA1 knockdown reduces the cisplatin-induced autophagy and sensitizes ovarian cancer cells to cisplatin. The Journal of toxicological sciences 19 26763392
2023 Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation. Nature communications 18 37993427
2019 Neurodevelopmental Disorders: Functional Role of Ambra1 in Autism and Schizophrenia. Molecular neurobiology 18 30915711
2018 CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling. The EMBO journal 18 30166453
2016 AMBRA1, a Novel BH3-Like Protein: New Insights Into the AMBRA1-BCL2-Family Proteins Relationship. International review of cell and molecular biology 18 28215535
2013 From gene to brain to behavior: schizophrenia-associated variation in AMBRA1 alters impulsivity-related traits. The European journal of neuroscience 18 23551272
2022 High-dose-androgen-induced autophagic cell death to suppress the Enzalutamide-resistant prostate cancer growth via altering the circRNA-BCL2/miRNA-198/AMBRA1 signaling. Cell death discovery 17 35318303
2022 Ambra1 haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration. Autophagy 17 35875981
2023 Ambra1 in exosomes secreted by HK-2 cells damaged by supersaturated oxalate induce mitophagy and autophagy-ferroptosis in normal HK-2 cells to participate in the occurrence of kidney stones. Biochimica et biophysica acta. Molecular cell research 16 37806389
2015 AMBRA1: When autophagy meets cell proliferation. Autophagy 16 26101901
2021 Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration. The British journal of dermatology 15 34773645
2015 AMBRA1-induced mitophagy: A new mechanism to cope with cancer? Molecular & cellular oncology 15 27308437
2019 AMBRA1-mediated autophagy and apoptosis associated with an epithelial-mesenchymal transition in the development of cleft palate induced by all-trans retinoic acid. Annals of translational medicine 13 31157249
2012 Dismantling the autophagic arsenal when it is time to die: concerted AMBRA1 degradation by caspases and calpains. Autophagy 13 22575990
2025 Redox-Induced Stabilization of AMBRA1 by USP7 Promotes Intestinal Oxidative Stress and Colitis Through Antagonizing DUB3-Mediated NRF2 Deubiquitination. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 39887666
2024 The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization. Cell reports 12 39207901
2021 AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination. International journal of molecular sciences 12 34769507
2019 Ambra1 inhibits paclitaxel-induced apoptosis in breast cancer cells by modulating the Bim/mitochondrial pathway. Neoplasma 12 30784282
2015 AMBRA1-regulated autophagy in vertebrate development. The International journal of developmental biology 12 26374532
2024 Urolithin A attenuates Doxorubicin-induced cardiotoxicity by enhancing PINK1-regulated mitophagy via Ambra1. Chemico-biological interactions 11 39725191
2023 Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma. Journal for immunotherapy of cancer 11 36868570
2022 Ambra1 in cancer: implications for clinical oncology. Apoptosis : an international journal on programmed cell death 11 35994214
2022 The Cancermuts software package for the prioritization of missense cancer variants: a case study of AMBRA1 in melanoma. Cell death & disease 11 36243772
2021 Aloe-emodin derivative produces anti-atherosclerosis effect by reinforcing AMBRA1-mediated endothelial autophagy. European journal of pharmacology 11 34800465
2021 The role of ambra1 in Pb-induced developmental neurotoxicity in zebrafish. Biochemical and biophysical research communications 11 35085890
2016 Nerve growth factor and autophagy: effect of nasal anti-NGF-antibodies administration on Ambra1 and Beclin-1 expression in rat brain. Growth factors (Chur, Switzerland) 11 26728403
2021 The Long-Lost Ligase: CRL4AMBRA1 Regulates the Stability of D-Type Cyclins. DNA and cell biology 10 34495753
2017 AMBRA1 is involved in T cell receptor-mediated metabolic reprogramming through an ATG7-independent pathway. Biochemical and biophysical research communications 9 28789945
2014 Ambra1 modulates starvation-induced autophagy through AMPK signaling pathway in cardiomyocytes. Biochemical and biophysical research communications 9 25117440
2024 Downregulation of Ambra1 by altered DNA methylation exacerbates dopaminergic neuron damage in a fenpropathrin-induced Parkinson-like mouse model. Ecotoxicology and environmental safety 8 38245935
2024 AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner. Cell death and differentiation 8 38424148
2024 Src inhibition modulates AMBRA1-mediated mitophagy to counteract endothelial-to-mesenchymal transition in renal allograft fibrosis. Cell proliferation 8 38943534
2021 The pro-autophagic protein AMBRA1 coordinates cell cycle progression by regulating CCND (cyclin D) stability. Autophagy 8 34657573
2019 Mitsugumin 53 promotes mitochondrial autophagy through regulating Ambra1 expression in C2C12 myoblast cells. Cell biology international 8 30614598
2019 AMBRA1, Autophagy, and the Extreme Male Brain Theory of Autism. Autism research and treatment 8 31687209
2025 Vitamin D sensitizes cervical cancer to radiation-induced apoptosis by inhibiting autophagy through degradation of Ambra1. Cell death discovery 7 39753527
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 7 37464439
2022 AMBRA1 promotes dsRNA- and virus-induced apoptosis through interacting with and stabilizing MAVS. Journal of cell science 7 34859815
2014 Autophagy regulation: RNF2 targets AMBRA1. Cell research 7 25104734
2023 Chemogenetic rectification of the inhibitory tone onto hippocampal neurons reverts autistic-like traits and normalizes local expression of estrogen receptors in the Ambra1+/- mouse model of female autism. Translational psychiatry 6 36804922
2023 AMBRA1 phosphorylation by CDK1 and PLK1 regulates mitotic spindle orientation. Cellular and molecular life sciences : CMLS 6 37584777
2023 Autophagy genes AMBRA1 and ATG8 play key roles in midgut remodeling of the yellow fever mosquito, Aedes aegypti. Frontiers in insect science 6 38469502
2021 AMBRA1 has an impact on melanoma development beyond autophagy. Autophagy 6 34156327
2018 The Clinicopathological Significance and Correlative Signaling Pathways of an Autophagy-Related Gene, Ambra1, in Breast Cancer: a Study of 25 Microarray RNA-Seq Datasets and in-House Gene Silencing. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 6 30476925