Affinage

ATF6

Cyclic AMP-dependent transcription factor ATF-6 alpha · UniProt P18850

Length
670 aa
Mass
74.6 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATF6 is an ER-resident type II transmembrane bZIP transcription factor that serves as a central sensor and effector of the unfolded protein response (UPR), integrating ER proteostasis with diverse developmental and stress-adaptive transcriptional programs. Under basal conditions, ATF6 is retained in the ER through BiP binding to its luminal domain and inter-chain disulfide bonds (C467 and C618); upon ER stress, disulfide reduction and BiP dissociation permit trafficking to the Golgi, where sequential cleavage by S1P/SKI-1 and S2P releases the ~50 kDa N-terminal fragment (p50ATF6) that translocates to the nucleus and activates ERSE- and ERSE-II-containing promoters in cooperation with NF-Y, driving expression of ER chaperones (BiP/GRP78), XBP1 mRNA, ERAD components, and oxidative stress defense genes such as catalase (PMID:10866666, PMID:11850408, PMID:14970232, PMID:31852864, PMID:27932512). ATF6 is additionally activated through its transmembrane domain by sphingolipids (dihydrosphingosine/dihydroceramide), independently of the luminal proteotoxic stress-sensing mechanism, and its activity is post-translationally tuned by RNF186-mediated K152 ubiquitination, OTUB1-mediated deubiquitination, and SIRT1-mediated deacetylation (PMID:30086303, PMID:34623328, PMID:33686769, PMID:30537742). Loss-of-function mutations in ATF6 cause achromatopsia with foveal hypoplasia, and ATF6 transcriptional targets extend beyond ER proteostasis to include tPA (systemic fibrinolysis), DAPK1 (IFN-γ-induced autophagy and antimicrobial defense), myocardin (smooth muscle differentiation), and osteocalcin, reflecting essential roles in retinal, cardiac, hepatic, immune, and skeletal biology (PMID:26029869, PMID:30504459, PMID:22874566, PMID:26105053, PMID:28377952).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1997 Medium

    ATF6 was first identified as a bZIP transcription factor that physically associates with SRF and contributes to serum-induced gene expression, establishing it as a nuclear transcriptional co-activator before its ER-stress role was known.

    Evidence Yeast two-hybrid, in vitro binding, reporter assays with ATF6-VP16 chimera and antisense ATF6

    PMID:9271374

    Open questions at the time
    • SRF interaction was not followed up in the context of later UPR studies
    • physiological relevance of ATF6-SRF axis unclear
  2. 2000 High

    The discovery that ATF6 undergoes stress-induced proteolytic cleavage to generate a soluble nuclear form that activates ERSE-dependent transcription in partnership with NF-Y redefined ATF6 as a transmembrane ER-stress sensor rather than a conventional transcription factor.

    Evidence Biochemical fractionation, immunofluorescence, reporter assays, ERSE mutagenesis, co-IP with YY1

    PMID:10866666

    Open questions at the time
    • Identity of the protease(s) performing cleavage was not yet established
    • mechanism of ER retention was unknown
  3. 2002 High

    Identification of S1P and S2P as the sequential Golgi proteases generating p50ATF6, together with evidence that BiP dissociation from the ATF6 luminal domain permits ER-to-Golgi trafficking, established the complete regulated intramembrane proteolysis (RIP) activation mechanism and the BiP-based stress-sensing model.

    Evidence S2P-deficient CHO cells, nuclear fractionation, reporter assays, BiP co-IP and transport studies

    PMID:11850408 PMID:12110159

    Open questions at the time
    • Whether additional ER-retention mechanisms exist beyond BiP binding
    • redox regulation of ATF6 not yet addressed
  4. 2002 High

    Characterization of the VN8 domain in the ATF6 N-terminus revealed a dual-function motif coupling transcriptional activation to rapid proteasomal degradation, explaining the transient nature of ATF6 signaling and linking it to ATF6 and XBP1 mRNA induction as convergent UPR outputs.

    Evidence Deletion/point mutagenesis, proteasome inhibitor treatment, pulse-chase; XBP1 splicing assays in IRE1α-null MEFs and S2P-deficient CHO cells

    PMID:11779464 PMID:11850408 PMID:11909875

    Open questions at the time
    • Ubiquitin ligase mediating VN8-dependent degradation was not identified
    • structural basis of VN8 activity unknown
  5. 2004 High

    Dissection of three distinct cis-elements (ERSE, ERSE-II, UPRE) clarified the division of labor between ATF6 and XBP1: ATF6 is sufficient for BiP/ERSE induction via NF-Y, while ERSE-II targets require both ATF6 and XBP1, and UPRE elements are XBP1-exclusive.

    Evidence XBP1-null MEFs, reporter assays, EMSA, NF-Y interaction analysis

    PMID:15598891

    Open questions at the time
    • Genome-wide mapping of ATF6-specific vs. shared targets not performed
    • chromatin context effects not addressed
  6. 2008 Medium

    VAPB was identified as a physical interactor that attenuates ATF6 transcriptional output, with the ALS-linked P56S mutant acting as a more potent inhibitor, providing a link between ATF6 regulation and neurodegenerative disease.

    Evidence Co-immunoprecipitation, reporter assays with wild-type and P56S VAPB overexpression

    PMID:18263603

    Open questions at the time
    • Mechanism by which VAPB suppresses ATF6 (retention, degradation?) is unresolved
    • no reciprocal validation or endogenous-level evidence
  7. 2009 High

    Demonstration that simulated ischemia activates ATF6 to induce GRP78 in cardiac myocytes, with dominant-negative ATF6 increasing ischemia/reperfusion cell death, established ATF6 as a cardioprotective effector beyond canonical ER-stress paradigms.

    Evidence Nuclear fractionation, EMSA/ChIP on GRP78 promoter, ATF6 dominant-negative and miRNA knockdown in primary cardiac myocytes

    PMID:19622751

    Open questions at the time
    • Full complement of cardiac ATF6 target genes not identified
    • in vivo cardiac phenotype of ATF6 loss not yet tested
  8. 2010 High

    Domain-swap experiments showed the ATF6 luminal tail is both necessary and sufficient for BiP-dependent ER retention and stress-regulated Golgi trafficking, distinguishing ATF6 from related ER-tethered transcription factors like CREB-H.

    Evidence Chimeric ATF6/CREB-H constructs, fluorescence microscopy, BiP co-IP, S1P cleavage assays

    PMID:19883396

    Open questions at the time
    • Whether glycosylation or other post-translational modifications of the luminal tail contribute to retention
  9. 2011 High

    The PERK/eIF2α/ATF4 pathway was shown to be required for both ATF6 protein synthesis and ATF6 trafficking to the Golgi, revealing cross-talk between two UPR branches at the level of ATF6 activation.

    Evidence Liver-specific PERK knockout mice, pulse-chase, subcellular fractionation

    PMID:21917591

    Open questions at the time
    • Whether PERK regulates ATF6 trafficking directly or via ATF4-induced gene products
  10. 2012 High

    ATF6 was found to directly bind the DAPK1 promoter downstream of IFN-γ signaling, driving autophagy induction; Atf6-knockout mice showed impaired autophagy and lethal susceptibility to bacterial infection, establishing ATF6 in innate immune defense.

    Evidence ChIP, promoter reporters, Atf6 KO mice with bacterial infection model, autophagy assays

    PMID:22874566

    Open questions at the time
    • Whether ATF6 cleaves in response to IFN-γ via canonical BiP-dependent mechanism or a distinct pathway
  11. 2015 Medium

    Multiple independent studies established ATF6 as a transcriptional regulator of developmental and differentiation programs — driving myocardin in smooth muscle differentiation, osteocalcin in osteoblastogenesis, and Runx2-dependent chondrocyte hypertrophy — extending ATF6 function well beyond ER-stress proteostasis.

    Evidence ChIP on myocardin/osteocalcin/ATF6 promoters, reporter assays, Runx2 co-IP, ES cell and chondrocyte differentiation models, siRNA and overexpression

    PMID:26105053 PMID:26374329 PMID:26527399 PMID:28377952

    Open questions at the time
    • Whether developmental ATF6 activation uses the same S1P/S2P cleavage mechanism
    • no single integrated model connecting ATF6 to differentiation signal transduction
  12. 2015 High

    Loss-of-function ATF6 mutations were identified as causative for achromatopsia with foveal hypoplasia, validated by attenuated UPR transcription in mutant assays and progressive photoreceptor dysfunction in Atf6-knockout mice, establishing ATF6 as essential for human cone photoreceptor development.

    Evidence Whole-exome sequencing of ACHM families, functional reporter assays, Atf6 KO mouse ERG and retinal morphology; subsequent classification of mutations into three mechanistic classes

    PMID:26029869 PMID:28028229

    Open questions at the time
    • Precise developmental window requiring ATF6 in cone specification not defined
    • whether sphingolipid-mediated ATF6 activation is relevant to retinal phenotype
  13. 2016 High

    ATF6 was shown to transcriptionally induce catalase and other oxidative stress defense genes by binding ERSE elements in their promoters; ATF6 KO mice had increased cardiac ischemia/reperfusion damage rescued by catalase overexpression, demonstrating ATF6 controls an antioxidant program beyond classical chaperone induction.

    Evidence ATF6 KO mice, I/R model, ChIP, gene array, AAV9-mediated ATF6 overexpression rescue

    PMID:27932512

    Open questions at the time
    • Whether the antioxidant program is ATF6-specific or shared with ATF6β
  14. 2018 High

    Discovery that sphingolipids (DHS/DHC) activate ATF6 through a transmembrane domain motif mechanistically distinct from the luminal proteotoxic stress-sensing pathway revealed a second, lipid-based activation mode and provided a druggable therapeutic strategy for ATF6-deficient achromatopsia.

    Evidence Site-directed TM domain mutagenesis, lipid addition, pathway-selective reporters, fenretinide treatment of ACHM mutant ATF6

    PMID:30086303

    Open questions at the time
    • Structural basis of sphingolipid-TM domain interaction unknown
    • whether lipid sensing operates through altered ATF6 oligomerization
  15. 2018 Medium

    ATF6 was identified as an 'off-switch' for IRE1: ATF6 loss leads to uncontrolled IRE1 upregulation and XBP1 hyper-splicing, revealing ATF6-dependent negative feedback within the UPR that limits IRE1 signaling duration.

    Evidence shRNA knockdown, live-cell fluorescent UPR reporters, ATF6 N-terminal domain rescue

    PMID:30287689

    Open questions at the time
    • Target gene(s) through which ATF6 suppresses IRE1 not identified
    • single-lab finding awaiting independent confirmation
  16. 2018 High

    Hepatocyte-specific ATF6 knockout demonstrated that ATF6 directly drives tPA (Plat) transcription, controlling systemic fibrinolytic capacity, while pharmacological ATF6 activation in iPSCs suppresses pluripotency and directs mesodermal differentiation, confirming non-proteostatic developmental roles.

    Evidence Hepatocyte-specific ATF6 KO mice, ChIP, bleeding/thrombosis assays; ATF6 agonist AA147 treatment of iPSCs and ACHM patient iPSCs, transcriptomics

    PMID:29440509 PMID:30504459

    Open questions at the time
    • Whether hepatic tPA regulation requires BiP-dependent ATF6 activation or basal ATF6 activity
    • iPSC differentiation effects not validated in vivo
  17. 2019 High

    Resolution of ATF6 disulfide-bonded oligomeric states (C467-dimer and C618-dimer) and demonstration that single disulfide reduction suffices for activation, with C618-dimers being more readily reduced, provided a molecular explanation for the rapidity and sensitivity of ATF6 stress sensing.

    Evidence ATF6α/ATF6β-deficient HCT116 cells, non-reducing SDS-PAGE, systematic cysteine mutagenesis

    PMID:31852864

    Open questions at the time
    • Identity of the reductase(s) acting on ATF6 disulfides in vivo
    • whether redox and BiP-dissociation sensing are coupled or independent
  18. 2021 High

    Identification of RNF186-mediated ubiquitination at K152 as an activating signal for ATF6 downstream of NOD2 in macrophages, and OTUB1 as a stabilizing deubiquitinase, established ubiquitin-dependent post-translational regulation of ATF6; RNF186 IBD risk variants impair this axis, linking ATF6 to inflammatory bowel disease susceptibility.

    Evidence Ubiquitination assays with K152 mutagenesis, RNF186 and ATF6 KO mice, Salmonella challenge; OTUB1 CRISPR ablation, xenograft model

    PMID:33686769 PMID:34623328

    Open questions at the time
    • Whether RNF186-mediated ubiquitination promotes ATF6 trafficking or cleavage specifically
    • whether OTUB1 acts directly on ATF6 or through an intermediary E3 ligase
  19. 2021 High

    ATF6 was shown to be required for efficient clearance of misfolded P23H rhodopsin, with Atf6 loss leading to protein accumulation and accelerated retinal degeneration, directly connecting ATF6's ERAD-enhancing transcriptional program to in vivo photoreceptor proteostasis.

    Evidence Atf6 KO × P23H rhodopsin knock-in mice, immunoblot, qPCR, ERG, IRE1 pathway analysis

    PMID:34381136

    Open questions at the time
    • Specific ERAD components upregulated by ATF6 in photoreceptors not identified
    • whether pharmacological ATF6 activation can rescue P23H degeneration
  20. 2022 Medium

    Pharmacological ATF6 activation was demonstrated to enhance ER proteostasis broadly — correcting folding of GABAA receptor variants and alpha-1-antitrypsin deficiency variants — validating ATF6 as a druggable target for conformational diseases beyond the retina.

    Evidence Small-molecule ATF6 activators (AA147), surface biotinylation, electrophysiology (GABAA); NE inhibition assays, polymer ELISA across 71 AATD variants with machine learning

    PMID:35477478 PMID:36630963

    Open questions at the time
    • Long-term effects of sustained pharmacological ATF6 activation on ER homeostasis unknown
    • whether ATF6 activation exerts proteotoxic stress in non-disease cells at therapeutic doses

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the dual (luminal proteotoxic vs. transmembrane lipid) activation modes, the identity of the reductase(s) acting on ATF6 disulfide bonds, the full genome-wide target spectrum distinguishing ATF6α from ATF6β, and whether pharmacological ATF6 modulation can treat achromatopsia, IBD, or conformational diseases in human patients.
  • No crystal or cryo-EM structure of full-length ATF6
  • ATF6α vs. ATF6β target gene specificity not systematically resolved
  • clinical translation of ATF6 agonists not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 10 GO:0140110 transcription regulator activity 10
Localization
GO:0005634 nucleus 6 GO:0005783 endoplasmic reticulum 5 GO:0005794 Golgi apparatus 4
Pathway
R-HSA-8953897 Cellular responses to stimuli 9 R-HSA-74160 Gene expression (Transcription) 8 R-HSA-1266738 Developmental Biology 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
HSPA5MBTPS1MBTPS2NFYAOTUB1RNF186RUNX2VAPB

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ATF6 transcriptionally induces XBP1 mRNA, which is then spliced by IRE1 to produce a potent UPR transcriptional activator; thus ATF6 and IRE1 pathways converge through XBP1 regulation. Reporter assays, Northern blot, IRE1α-null MEFs and S2P-deficient CHO cells (genetic epistasis), splicing assays Cell High 11779464 11850408
2000 ATF6 activates the ER stress response element (ERSE) as a transcription factor; upon ER stress (thapsigargin), ATF6 undergoes proteolytic cleavage to generate a faster-migrating soluble nuclear form that drives ERSE-dependent transcription. Optimal activation requires NF-Y binding to ERSE and YY1 interacts with ATF6 to enhance its activity. Biochemical fractionation, immunofluorescence, reporter/luciferase assays, co-immunoprecipitation (YY1–ATF6), mutagenesis of ERSE Molecular and cellular biology High 10866666
1997 ATF6, a bZIP protein, physically interacts with the transcriptional activation domain of serum response factor (SRF); ATF6-VP16 chimera activates SRE reporters and antisense ATF6 reduces serum-induced c-fos expression, placing ATF6 as a co-activator in SRF-mediated transcription. Yeast two-hybrid screen, in vitro binding assay, reporter assay, antisense construct Molecular and cellular biology Medium 9271374
2002 ATF6 is cleaved at the Golgi by Site-1 protease (S1P) and Site-2 protease (S2P), generating the active N-terminal p50ATF6 fragment that translocates to the nucleus to activate UPR target genes; S2P-deficient CHO cells fail to cleave ATF6 or activate downstream UPR transcription. S2P-deficient CHO cell genetic system, immunoblot, nuclear fractionation, reporter assays Genes & development High 11850408
2002 BiP (GRP78) dissociation from ATF6's luminal domain initiates ATF6 transport to the Golgi for proteolytic activation; BiP binding retains ATF6 in the ER and senses the ER folding capacity. Commentary on co-immunoprecipitation and transport studies showing BiP–ATF6 interaction and its stress-regulated release Developmental cell Medium 12110159
2002 The N-terminal 93 amino acids of ATF6 contain a VP16-homologous VN8-like domain required for both transcriptional activation and rapid proteasomal degradation of ATF6; point mutations in VN8 abolish transcription and increase ATF6 half-life. Deletion and point mutant constructs, reporter assays, proteasome inhibitor treatment, pulse-chase The Journal of biological chemistry High 11909875
2002 Nitric oxide-induced ER stress causes proteolytic cleavage of p90ATF6 to p50ATF6, which translocates to the nucleus and binds the ERSE of the CHOP gene, driving CHOP expression and apoptosis in macrophages; overexpression of p50ATF6 alone induces cell death reversed by dominant-negative CHOP. Immunoblot, nuclear fractionation, EMSA, reporter assay, transfection with p90/p50ATF6 expression plasmids, CHOP-knockout macrophages The Journal of biological chemistry High 11805088
2004 ATF6 differentially activates ERSE (requiring NF-Y), UPRE (does not bind ATF6; XBP1-dependent), and ERSE-II (NF-Y-dependent ATF6 binding plus NF-Y-independent XBP1 binding); ATF6 alone is sufficient to drive BiP/ERSE transcription without XBP1, while Herp/ERSE-II induction requires both. XBP1-null MEFs, reporter assays, EMSA, NF-Y interaction assays Journal of biochemistry High 15598891
2004 SKI-1/S1P is the first protease that cleaves ATF6 at the Golgi; protein-based inhibitors (alpha-1-antitrypsin variants and prosegment mutant R134E) block SKI-1 and reduce ATF6 processing by >55%, forming SDS-stable complexes with SKI-1. Transient transfection, stable cell lines, immunoblot of SREBP-2 and ATF6 processing, SDS-PAGE complex formation The Journal of biological chemistry High 14970232
2008 VAPB (and VAPA) MSP domain physically interacts with ATF6; overexpression of VAPB or the ALS-associated VAPB-P56S mutant attenuates ATF6-regulated transcription, with VAPB-P56S being a more potent inhibitor. Co-immunoprecipitation, reporter assays, overexpression of VAPB/VAPB(P56S) Human molecular genetics Medium 18263603
2009 Simulated ischemia activates ATF6 in cardiac myocytes, causing its translocation from ER to nucleus where it binds an ERSE in the GRP78 promoter to drive GRP78 expression; dominant-negative ATF6 or ATF6-targeted miRNA blocks ischemia-induced GRP78 induction and increases cell death upon reperfusion. Nuclear fractionation, EMSA/ChIP, ATF6 dominant-negative and miRNA knockdown, primary cardiac myocyte model The Journal of biological chemistry High 19622751
2010 ATF6 luminal tail contains the BiP-binding and ER-retention determinants for stress sensing and Golgi trafficking; in contrast to the related CREB-H whose ER retention depends on a cytoplasmic motif, transferring ATF6's luminal tail onto an ERM-deficient CREB-H chimera restores ER retention. Chimeric protein constructs, subcellular localization by fluorescence microscopy, BiP co-immunoprecipitation, S1P cleavage assays Traffic (Copenhagen, Denmark) High 19883396
2011 The PERK/eIF2α/ATF4 integrated stress response pathway is required for both ATF6 protein synthesis and ATF6 trafficking from the ER to the Golgi for intramembrane proteolysis; liver-specific PERK depletion markedly reduces ATF6 activation and downstream chaperone expression. Liver-specific PERK knockout mice, pulse-chase protein synthesis, subcellular fractionation, immunoblot Molecular biology of the cell High 21917591
2015 ACHM-associated ATF6 mutations define three mechanistic classes: class 1 impairs ER-to-Golgi trafficking and regulated intramembrane proteolysis; class 2 produces constitutively active cytosolic ATF6 with intact transcriptional activity even without ER stress; class 3 has complete loss of bZIP-dependent transcriptional activity. Patient fibroblasts with class 1 or 3 mutations show increased death under ER stress. Functional characterization of recombinant mutant ATF6 proteins, trafficking assays, reporter assays, patient-derived primary fibroblasts Proceedings of the National Academy of Sciences of the United States of America High 28028229
2015 Loss-of-function mutations in ATF6 attenuate ATF6 transcriptional activity in response to ER stress and cause achromatopsia with foveal hypoplasia; Atf6-/- mice develop progressive rod and cone dysfunction, establishing ATF6 as essential for cone photoreceptor function and foveal development. Whole-exome sequencing, functional reporter assays of mutant ATF6, Atf6 knockout mouse ERG and retinal morphology Nature genetics High 26029869
2016 ATF6 activation in cardiac myocytes subjected to ischemia/reperfusion induces oxidative stress response genes (including catalase) by binding ER stress response elements in their promoters; ATF6 knockout mice show increased I/R damage and decreased catalase induction, while ATF6 overexpression or catalase overexpression restores protection. ATF6 knockout mice, I/R model, gene array, ChIP, promoter reporter assays, AAV9-mediated ATF6 overexpression Circulation research High 27932512
2018 ATF6 is activated by specific sphingolipids (dihydrosphingosine and dihydroceramide) through a transmembrane domain motif distinct from the luminal domain that senses proteotoxic stress; single mutations in this transmembrane motif abolish DHS/DHC activation while preserving proteotoxic stress activation. Site-directed mutagenesis of ATF6 transmembrane domain, lipid addition assays, pathway-selective reporters, fenretinide treatment of achromatopsia mutant ATF6 Developmental cell High 30086303
2018 ATF6 loss results in uncontrolled IRE1 upregulation and increased XBP1 splicing during ER stress; the transcriptionally active N-terminal ATF6 domain reverses IRE1 upregulation, identifying an ATF6-dependent 'off-switch' for IRE1 signaling. shRNA-mediated silencing, live-cell fluorescent UPR reporters, ATF6 N-terminal domain overexpression, IRE1 inhibition The Journal of biological chemistry Medium 30287689
2019 ATF6 disulfide-bonded oligomeric forms in the ER exist as two types of dimers (C467-dimer and C618-dimer); all forms including monomer are activated by single reduction of a disulfide bond in response to ER stress, with C618-dimer being more easily reduced, ensuring rapidity of ATF6α activation. ATF6α/ATF6β-deficient HCT116 cells, non-reducing SDS-PAGE, cysteine mutagenesis (C467A, C618A), disulfide bond analysis Cell structure and function High 31852864
2007 ER stressors transcriptionally upregulate ATF6 mRNA through a positive feedback loop: the active p50-ATF6 fragment binds ATF6-binding elements in the ATF6 gene's own promoter; S1P inhibition blocks this upregulation. RT-PCR, mRNA stability assay, S1P inhibitor, promoter analysis Biochemical and biophysical research communications Medium 17307147
2015 miR-424 directly targets the 3'UTR of ATF6 mRNA and attenuates ATF6 transcriptional activity during UPR; PERK-mediated downregulation of the miR-424(322)-503 cluster during ER stress de-represses ATF6, enabling optimal ATF6 activation. Luciferase 3'UTR reporter, PERK-deficient MEFs, selective PERK activator, IRE1 inhibitor, siRNA knockdown Scientific reports Medium 26674075
2021 The E3 ubiquitin ligase RNF186 ubiquitinates ATF6 at K152 upon NOD2 stimulation in human macrophages, promoting UPR activation, cytokine secretion, and antimicrobial responses; RNF186 IBD risk variants reduce this ubiquitination and impair UPR-associated signaling. Atf6-deficient mice show reduced UPR in colonic tissues and impaired bacterial clearance. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K152), ATF6 and RNF186 knockout mice, Salmonella challenge model The Journal of clinical investigation High 34623328
2021 The deubiquitinase OTUB1 stabilizes ATF6 by inhibiting its ubiquitylation in bladder cancer cells, thereby sustaining ATF6 signaling and transcriptional activity; OTUB1 ablation reduces ATF6-dependent transcription and impairs cancer cell proliferation. Luciferase pathway screening, co-immunoprecipitation, ubiquitylation assay, siRNA/CRISPR ablation, in vivo xenograft Cancer science Medium 33686769
2018 ATF6 suppresses cardiac fibroblast activation by the TGFβ-Smad pathway; ATF6 activation reduces fibroblast contraction and αSMA induction, while ATF6 silencing or deletion hyperactivates fibroblasts; in vivo ATF6 reduces cardiac fibrosis. ATF6 conditional knockout mice, siRNA silencing, TGFβ stimulation, contraction assay, αSMA immunostaining, Smad pathway analysis International journal of molecular sciences Medium 32085622
2012 ATF6 directly binds the DAPK1 gene promoter CRE/ATF site (in association with C/EBPβ) downstream of IFN-γ signaling; IFN-γ-stimulated proteolytic cleavage of ATF6 is required for DAPK1 expression and subsequent autophagy induction. Atf6-/- mice fail to induce autophagy in response to IFN-γ and are highly susceptible to lethal bacterial infections. ChIP, promoter reporter assays, Atf6 knockout mice, bacterial infection model, autophagy assays Autophagy High 22874566
2015 DKK3 activates ATF6 (as a secreted cytokine), leading to increased ATF6 binding to the myocardin promoter and upregulation of myocardin expression, driving smooth muscle cell differentiation from embryonic stem cells; ERK1/2 inhibition further promotes ATF6 expression and myocardin transcription. ChIP (ATF6 on myocardin promoter), reporter assays, overexpression, siRNA knockdown, ES cell differentiation model The Journal of biological chemistry Medium 26105053
2015 ATF6 associates with Runx2 via co-immunoprecipitation and enhances Runx2-mediated chondrocyte hypertrophy and endochondral bone growth; overexpression of ATF6 accelerates chondrocyte differentiation while siRNA knockdown inhibits it; the promotive effect requires Runx2. Co-immunoprecipitation (ATF6–Runx2), siRNA knockdown, adenoviral overexpression, micromass cultures, fetal bone explants Journal of orthopaedic surgery and research Medium 26374329
2015 Runx2 transcriptionally activates the ATF6 gene through Runx2-binding elements in the ATF6 promoter, while Sox6 represses ATF6 expression; ATF6a (cleaved active form) acts as a co-factor of Runx2 to augment hypertrophic chondrocyte differentiation and modulates IHH/PTHrP signaling. Promoter reporter assays, ChIP, siRNA knockdown of Runx2/Sox6, adenoviral ATF6a overexpression, chondrogenesis assays Journal of cell science Medium 26527399
2018 SIRT1 deacetylates and inactivates ATF6; ATF6 in turn can bind the SIRT1 promoter to regulate SIRT1 transcription, forming a feedback loop; SIRT1/ATF6-dependent mechanism controls lipid droplet accumulation in hepatocytes. ChIP, co-immunoprecipitation, proximity ligation assay, dual luciferase reporter, siRNA and overexpression of SIRT1 and ATF6 Cellular physiology and biochemistry Medium 30537742
2018 ATF6 pharmacological activation (using small-molecule agonist AA147) in human iPSC-derived cells suppresses pluripotency and directs mesodermal cell fate differentiation; iPSCs from ATF6-mutant achromatopsia patients show impaired differentiation, demonstrating a developmental role for ATF6 beyond ER stress. Small-molecule ATF6 agonist activation, patient-derived ATF6-mutant iPSCs, germ-layer differentiation assays, transcriptomics Science signaling High 29440509
2020 ATF6 shapes early CHOP dynamics during UPR; ATF6 siRNA knockdown alters CHOP induction kinetics, confirmed by dynamic mathematical modeling calibrated against single-cell fluorescence microscopy of BAC-GFP reporter lines. siRNA knockdown, BAC-GFP reporter cell lines, live microscopy, dynamic mathematical modeling iScience Medium 32058971
2018 EDEM1 silencing stabilizes ATF6 protein and increases ATF6 export to the Golgi during ER stress, revealing that ATF6 is natively unstable and EDEM1 normally limits ATF6 bioavailability; an EDEM1 somatic variant (N198I) found in hepatocellular carcinoma alters ATF6 signaling. siRNA phenotypic screen, ATF6 protein stability assays, immunofluorescence of Golgi export The FEBS journal Medium 30281916
2021 ATF6 is required for efficient clearance of misfolded P23H rhodopsin in rod photoreceptors; Atf6-/- mice carrying P23H rhodopsin accumulate elevated rhodopsin protein (not mRNA) at early ages and develop accelerated retinal degeneration, with compensatory IRE1 hyperactivation. Atf6 knockout crossed with P23H rhodopsin knock-in mice, immunoblot, qPCR, ERG, IRE1 pathway analysis Scientific reports High 34381136
2018 ATF6 directly induces transcription of the tPA gene (Plat) in hepatocytes; hepatocyte-specific ATF6 knockout mice show decreased liver tPA, circulating tPA, and fibrinolytic activity; DACH1 corepressor represses ATF6 to downregulate tPA, establishing an ATF6-tPA axis controlling systemic fibrinolysis. Hepatocyte-specific ATF6 and DACH1 knockout mice, ChIP, reporter assays, bleeding time/thrombosis assays Blood High 30504459
2021 ATF6 interacts with the FGF2 promoter and promotes FGF2 transcription in chondrocytes; ATF6 inhibitor Ceapin-A7 blocks ATF6-FGF2-driven angiogenesis in vitro and angiogenesis-osteogenesis coupling in vivo in an ankylosing spondylitis model. ChIP (ATF6 on FGF2 promoter), reporter assays, ATF6 inhibitor Ceapin-A7, in vivo SKG mouse model iScience Medium 34296071
2015 Selective pharmacological activation of ATF6 preferentially reduces misfolded mutant rhodopsin (multiple RP-causing variants) with minimal effects on wild-type rhodopsin, demonstrating ATF6 activates a quality-control degradation program for misfolded ER clients. Inducible ATF6f expression system, wild-type vs. mutant rhodopsin co-expression, immunoblot Investigative ophthalmology & visual science Medium 22956602
2020 ATF6 promotes AIFM2 transcription by directly binding to both the p53 and AIFM2 gene promoters; ATF6 knockout in SAP mice attenuates acinar apoptosis and ER disorder, while AIFM2 overexpression can re-establish pathological features in ATF6-null SAP mice. ATF6 knockout mice (crossed with PRSS1 transgenic SAP model), ChIP-qPCR, luciferase reporter, adenovirus-mediated overexpression/knockdown, proteomics Theranostics High 32724472
2014 ATF6 translocates from cytoplasm to nucleus during odontoblast differentiation; ATF6 overexpression increases DSPP and DMP1 expression, alkaline phosphatase activity, and matrix mineralization; ATF6 inhibition decreases ALP activity, establishing ATF6 as a regulator of odontoblastic differentiation. Immunofluorescence/confocal microscopy (ATF6 translocation), adenoviral overexpression, siRNA inhibition, alizarin red staining, ALP assay Journal of dental research Medium 24570149
2022 Pharmacological ATF6 activation increases assembly, trafficking, and surface expression of variant GABAA receptors by remodeling ER proteostasis, specifically upregulating BiP and the trafficking receptor LMAN1 and enhancing their interactions with GABAA receptor subunits. Small-molecule ATF6 activators, co-immunoprecipitation (BiP/LMAN1 with GABAA subunits), surface biotinylation, electrophysiology Cell & bioscience Medium 35477478
2015 ATF6 binds the promoter of p50Atf6-responsive element in the osteocalcin (Bglap) gene; ChIP assay shows increased p50Atf6 binding to Bglap promoter upon MTA treatment; Atf6 shRNA knockdown abolishes MTA-induced mineralization, establishing an ATF6–osteocalcin axis in osteoblastogenesis. ChIP, luciferase reporter, Tet-on shRNA Atf6 knockdown, mineralization assay Bone reports Medium 28377952
2022 ATF6 pharmacological activation by small-molecule activators corrects folding and increases neutrophil elastase inhibitory activity of most alpha-1-antitrypsin deficiency variants (including Z-AAT), reducing polymer accumulation; machine learning identified the 'gate' area as an unexpected ATF6-responsive region. Pharmacological ATF6 activators (AA147), NE inhibition assay, polymer ELISA, Gaussian process machine learning across 71 AATD variants Cell chemical biology Medium 36630963

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 3312 11779464
2002 IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes & development 861 11850408
2013 Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell reports 462 23583182
2003 Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. Journal of hepatology 409 12713871
2004 Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. Journal of biochemistry 354 15598891
2011 The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Molecular biology of the cell 330 21917591
2000 ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1. Molecular and cellular biology 284 10866666
2016 ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart. Circulation research 265 27932512
2018 A lifetime of stress: ATF6 in development and homeostasis. Journal of biomedical science 214 29801500
2002 Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP. The Journal of biological chemistry 203 11805088
2015 Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nature genetics 183 26029869
2012 ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. Proceedings of the National Academy of Sciences of the United States of America 168 23011799
2015 Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nature communications 155 25754093
1997 Interaction of ATF6 and serum response factor. Molecular and cellular biology 149 9271374
2018 The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms. Developmental cell 140 30086303
2008 VAPB interacts with and modulates the activity of ATF6. Human molecular genetics 137 18263603
2009 Ischemia activates the ATF6 branch of the endoplasmic reticulum stress response. The Journal of biological chemistry 136 19622751
2020 Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation. Theranostics 117 32373236
2018 Activated ATF6 Induces Intestinal Dysbiosis and Innate Immune Response to Promote Colorectal Tumorigenesis. Gastroenterology 98 30063920
2012 The ATF6 branch of unfolded protein response and apoptosis are activated to promote African swine fever virus infection. Cell death & disease 98 22764100
2020 ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response. iScience 97 32058971
2018 ER stress signaling has an activating transcription factor 6α (ATF6)-dependent "off-switch". The Journal of biological chemistry 97 30287689
2016 The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma. Oncotarget 92 26716508
2013 ATF6 upregulates XBP1S and inhibits ER stress-mediated apoptosis in osteoarthritis cartilage. Cellular signalling 86 24269637
2017 Japanese encephalitis virus activates autophagy through XBP1 and ATF6 ER stress sensors in neuronal cells. The Journal of general virology 79 28535855
2018 miR-103/107 promote ER stress-mediated apoptosis via targeting the Wnt3a/β-catenin/ATF6 pathway in preadipocytes. Journal of lipid research 78 29483204
2013 Sustained IRE1 and ATF6 signaling is important for survival of melanoma cells undergoing ER stress. Cellular signalling 78 24240056
2020 ID1 confers cancer cell chemoresistance through STAT3/ATF6-mediated induction of autophagy. Cell death & disease 76 32080166
2020 ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis. Theranostics 75 32724472
2019 Proteostasis and Beyond: ATF6 in Ischemic Disease. Trends in molecular medicine 75 31078432
2018 ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells. Journal of neuroinflammation 75 30241539
2018 ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells. Cell discovery 72 29423270
2024 Molecular mechanism of ATF6 in unfolded protein response and its role in disease. Heliyon 69 38434326
2012 Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulation. Investigative ophthalmology & visual science 69 22956602
2013 Roles for ATF6 and the sarco/endoplasmic reticulum protein quality control system in the heart. Journal of molecular and cellular cardiology 66 24140798
2002 BiP binding keeps ATF6 at bay. Developmental cell 64 12110159
2002 Coordination of ATF6-mediated transcription and ATF6 degradation by a domain that is shared with the viral transcription factor, VP16. The Journal of biological chemistry 60 11909875
2018 The unfolded protein response regulator ATF6 promotes mesodermal differentiation. Science signaling 55 29440509
2018 Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 55 30537742
2017 β-elemene regulates endoplasmic reticulum stress to induce the apoptosis of NSCLC cells through PERK/IRE1α/ATF6 pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 54 28672279
2017 ATF6 knockdown decreases apoptosis, arrests the S phase of the cell cycle, and increases steroid hormone production in mouse granulosa cells. American journal of physiology. Cell physiology 51 28100484
2020 MiR-149 attenuates endoplasmic reticulum stress-induced inflammation and apoptosis in nonalcoholic fatty liver disease by negatively targeting ATF6 pathway. Immunology letters 50 32194141
2017 Matrine attenuates cardiac fibrosis by affecting ATF6 signaling pathway in diabetic cardiomyopathy. European journal of pharmacology 50 28373137
2008 Coping with the stress: expression of ATF4, ATF6, and downstream targets in organs of hibernating ground squirrels. Archives of biochemistry and biophysics 50 18541136
2022 Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes. Nature communications 49 36216837
2019 Characterization of Retinal Structure in ATF6-Associated Achromatopsia. Investigative ophthalmology & visual science 49 31237654
2017 Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation. World journal of gastroenterology 49 28246472
2016 Achromatopsia mutations target sequential steps of ATF6 activation. Proceedings of the National Academy of Sciences of the United States of America 47 28028229
2019 Seneca valley virus activates autophagy through the PERK and ATF6 UPR pathways. Virology 46 31539773
2004 Development of protein-based inhibitors of the proprotein of convertase SKI-1/S1P: processing of SREBP-2, ATF6, and a viral glycoprotein. The Journal of biological chemistry 46 14970232
2020 Intersection of the ATF6 and XBP1 ER stress pathways in mouse islet cells. The Journal of biological chemistry 44 32788214
2023 Tumor-associated macrophages confer colorectal cancer 5-fluorouracil resistance by promoting MRP1 membrane translocation via an intercellular CXCL17/CXCL22-CCR4-ATF6-GRP78 axis. Cell death & disease 41 37658050
2015 PERK regulated miR-424(322)-503 cluster fine-tunes activation of IRE1 and ATF6 during Unfolded Protein Response. Scientific reports 40 26674075
2007 Transcriptional activation of ATF6 by endoplasmic reticulum stressors. Biochemical and biophysical research communications 40 17307147
2021 p62-Induced Cancer-Associated Fibroblast Activation via the Nrf2-ATF6 Pathway Promotes Lung Tumorigenesis. Cancers 39 33670717
2018 Alterations of EDEM1 functions enhance ATF6 pro-survival signaling. The FEBS journal 36 30281916
2015 Dickkopf Homolog 3 Induces Stem Cell Differentiation into Smooth Muscle Lineage via ATF6 Signalling. The Journal of biological chemistry 36 26105053
2021 OTUB1 facilitates bladder cancer progression by stabilizing ATF6 in response to endoplasmic reticulum stress. Cancer science 34 33686769
2014 Transcriptional factor ATF6 is involved in odontoblastic differentiation. Journal of dental research 33 24570149
2023 CYP2E1 triggered GRP78/ATF6/CHOP signaling axis inhibit apoptosis and promotes progression of hepatocellular carcinoma. Archives of biochemistry and biophysics 32 37499993
2022 The impact of Nrf2/HO-1, caspase-3/Bax/Bcl2 and ATF6/IRE1/PERK/GRP78 signaling pathways in the ameliorative effects of morin against methotrexate-induced testicular toxicity in rats. Molecular biology reports 32 36057755
2021 ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model. Scientific reports 32 34381136
2013 A missense polymorphism in ATF6 gene is associated with susceptibility to hepatocellular carcinoma probably by altering ATF6 level. International journal of cancer 31 24302549
2021 Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response. The Journal of clinical investigation 30 34623328
2018 ER Stress Activates the TOR Pathway through Atf6. Journal of molecular signaling 30 30210580
2018 An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1. Blood 29 30504459
2012 IFNG and autophagy: a critical role for the ER-stress mediator ATF6 in controlling bacterial infections. Autophagy 29 22874566
2022 Gremlin-1 Promotes Colorectal Cancer Cell Metastasis by Activating ATF6 and Inhibiting ATF4 Pathways. Cells 28 35883579
2016 Quinocetone triggered ER stress-induced autophagy via ATF6/DAPK1-modulated mAtg9a trafficking. Cell biology and toxicology 27 27085326
2020 MiR-185-5p ameliorates endoplasmic reticulum stress and renal fibrosis by downregulation of ATF6. Laboratory investigation; a journal of technical methods and pathology 26 32514126
2020 The role of ATF6 in Cr(VI)-induced apoptosis in DF-1 cells. Journal of hazardous materials 26 33243643
2015 Transmission of ER stress response by ATF6 promotes endochondral bone growth. Journal of orthopaedic surgery and research 26 26374329
2022 Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors. Cell & bioscience 25 35477478
2020 The ATF6-EGF Pathway Mediates the Awakening of Slow-Cycling Chemoresistant Cells and Tumor Recurrence by Stimulating Tumor Angiogenesis. Cancers 25 32630838
2015 ER stress related factor ATF6 and caspase-12 trigger apoptosis in neonatal hypoxic-ischemic encephalopathy. International journal of clinical and experimental pathology 25 26261584
2022 Luteolin restricts ASFV replication by regulating the NF-κB/STAT3/ATF6 signaling pathway. Veterinary microbiology 24 35961273
2021 ATF6 aggravates angiogenesis-osteogenesis coupling during ankylosing spondylitis by mediating FGF2 expression in chondrocytes. iScience 24 34296071
2021 IL-6/STAT3 Induced Neuron Apoptosis in Hypoxia by Downregulating ATF6 Expression. Frontiers in physiology 24 34744770
2020 The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts. International journal of molecular sciences 24 32085622
2018 Polysaccharide from Angelica sinensis protects H9c2 cells against oxidative injury and endoplasmic reticulum stress by activating the ATF6 pathway. The Journal of international medical research 24 29517941
2021 ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy-Dependent Pathway. Frontiers in immunology 23 33679742
2015 miRNA-221 is elevated in cystic fibrosis airway epithelial cells and regulates expression of ATF6. Molecular and cellular pediatrics 23 26542291
2020 Establishment and validation of an endoplasmic reticulum stress reporter to monitor zebrafish ATF6 activity in development and disease. Disease models & mechanisms 22 31852729
2019 Psoralen induces hepatic toxicity through PERK and ATF6 related ER stress pathways in HepG2 cells. Toxicology mechanisms and methods 22 31364909
2017 Avian metapneumovirus subgroup C induces autophagy through the ATF6 UPR pathway. Autophagy 22 28949785
2023 A new insight into fluoride induces cardiotoxicity in chickens: Involving the regulation of PERK/IRE1/ATF6 pathway and heat shock proteins. Toxicology 21 38036095
2019 Non-Structural Protein 2B of Human Rhinovirus 16 Activates Both PERK and ATF6 Rather Than IRE1 to Trigger ER Stress. Viruses 21 30717233
2015 ATF6a, a Runx2-activable transcription factor, is a new regulator of chondrocyte hypertrophy. Journal of cell science 20 26527399
2020 Multiexon deletion alleles of ATF6 linked to achromatopsia. JCI insight 19 32271167
2010 Different mechanisms of recognition and ER retention by transmembrane transcription factors CREB-H and ATF6. Traffic (Copenhagen, Denmark) 19 19883396
2023 Protocadherin 20 maintains intestinal barrier function to protect against Crohn's disease by targeting ATF6. Genome biology 18 37407995
2019 Reinvestigation of Disulfide-bonded Oligomeric Forms of the Unfolded Protein Response Transducer ATF6. Cell structure and function 18 31852864
2022 AA147 ameliorates post-cardiac arrest cerebral ischemia/reperfusion injury through the co-regulation of the ATF6 and Nrf2 signaling pathways. Frontiers in pharmacology 17 36506549
2021 JAK2/STAT3 inhibitor reduced 5-FU resistance and autophagy through ATF6-mediated ER stress. Journal of receptor and signal transduction research 17 33599179
2014 Explore on the effect of ATF6 on cell growth and apoptosis in cartilage development. Histochemistry and cell biology 17 24934104
2025 Embelin improves alcoholic steatohepatitis in alcohol-associated liver disease via ATF6-mediated P2X7r-NLRP3 signaling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 16 40106966
2015 Mineral trioxide aggregate induces osteoblastogenesis via Atf6. Bone reports 16 28377952
2023 Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis. Cell chemical biology 15 36630963
2023 Unfolded protein response factor ATF6 augments T helper cell responses and promotes mixed granulocytic airway inflammation. Mucosal immunology 15 37209959
2023 PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6. iScience 14 36824269