Affinage

ATF6

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

Length
670 aa
Mass
74.6 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATF6 is an ER-resident basic-leucine zipper transcription factor that serves as one of the three principal effector arms of the unfolded protein response, converting ER stress into a transcriptional program that restores proteostasis (PMID:10856300, PMID:11779464). Under homeostatic conditions ATF6 is retained in the ER through binding by the chaperone BiP/GRP78, whose dissociation upon ER stress licenses ATF6 trafficking to the Golgi for regulated intramembrane proteolysis (PMID:12110159). ATF6 carries two mechanistically separable activation inputs: a luminal-domain pathway responsive to proteotoxic stress and a transmembrane-domain pathway activated by the sphingolipids dihydrosphingosine and dihydroceramide (PMID:30086303). Proteolytic release of the N-terminal fragment generates a nuclear transcription factor that binds ATF6-consensus/ERSE elements; this same N-terminal region contains a VP16-like (VN8) domain that couples potent transactivation to rapid proteasomal turnover (PMID:11909875). The cleaved fragment drives chaperone and proteostasis genes and induces XBP1, integrating the ATF6 and IRE1 arms while also acting as a negative off-switch that restrains IRE1/XBP1s signaling (PMID:11779464, PMID:30287689, PMID:23583182). Beyond canonical UPR targets, ATF6 directly induces tissue- and context-specific genes including catalase for oxidative-stress defense (PMID:27932512), RHEB to activate mTORC1 during cardiac hypertrophy (PMID:30582446), and tPA (Plat) for hepatic fibrinolysis (PMID:30504459), and it suppresses lipogenesis by binding SREBP2 through its leucine zipper to recruit HDAC1 (PMID:14765107). ATF6 activity is tuned by post-translational control: p38 MAPK phosphorylation of a threonine upstream of the DNA-binding domain is required for Golgi processing (PMID:25135476), while ubiquitination at K152 by RNF186, deubiquitination/stabilization by OTUB1, and degradation via a GRINA-HRD1 complex set ATF6 abundance and signaling output (PMID:34623328, PMID:33686769, PMID:39855351). Loss-of-function ATF6 mutations cause achromatopsia and impair cone photoreceptor development, with disease alleles falling into trafficking-defective, constitutively active, and transactivation-dead classes (PMID:28028229, PMID:34561305).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 Medium

    Established ATF6 as a transcriptional cofactor before its UPR role was known, by showing it physically engages SRF to support serum-induced immediate-early gene expression.

    Evidence Yeast two-hybrid screen, in vitro binding, and SRE reporter/antisense assays

    PMID:9271374

    Open questions at the time
    • Does not connect ATF6 to ER stress or membrane regulation
    • Single lab, no structural characterization of the SRF interface
  2. 2000 High

    Defined ATF6 as a direct transcriptional effector of ER stress with its own consensus DNA element, and placed it downstream of IRE1, answering what ATF6 actually does during the UPR.

    Evidence Reporter assays, dominant-negative and GAL4-fusion constructs, epistasis with hIRE1

    PMID:10856300

    Open questions at the time
    • Did not establish the proteolytic activation mechanism
    • Endogenous target gene repertoire not yet mapped
  3. 2001 High

    Linked the ATF6 and IRE1 arms by showing ATF6 induces XBP1 transcription, with only IRE1-spliced XBP1 yielding an active factor, defining pathway ordering within the UPR.

    Evidence Reporter assays, Northern/Western blotting, identification of spliced XBP1

    PMID:11779464

    Open questions at the time
    • Direct ATF6 binding to the XBP1 promoter not yet shown (addressed later)
    • Functional division of labor between the two arms unresolved
  4. 2002 High

    Explained how ATF6 is held inactive and how activation begins, identifying BiP retention in the ER and stress-induced dissociation as the trigger for Golgi trafficking, and identifying the VN8 domain that couples transactivation to rapid degradation.

    Evidence Co-IP/trafficking work (cited commentary) and VN8 deletion/point mutagenesis with half-life and proteasome assays

    PMID:11909875 PMID:12110159

    Open questions at the time
    • The S1P/S2P proteolysis step itself not characterized in these entries
    • Identity of the ubiquitin machinery acting on ATF6 unknown at this time
  5. 2004 High

    Revealed a non-canonical repressive function: cleaved ATF6 directly binds SREBP2 via its leucine zipper and recruits HDAC1 to suppress lipogenic transcription, tying nutrient/ER status to lipid metabolism.

    Evidence GST pull-down, co-IP, ChIP, and reporter assays with BiP-overexpression reversal

    PMID:14765107

    Open questions at the time
    • Physiological contexts where this repression dominates not defined
    • Structural basis of the bZIP-SREBP2 heterodimer unresolved
  6. 2007 Medium

    Showed ATF6 autoregulates its own promoter through cleaved p50-ATF6, establishing a positive feedback loop that amplifies the UPR response.

    Evidence RT-PCR, promoter reporter assay, S1P inhibitor treatment

    PMID:17307147

    Open questions at the time
    • Direct ChIP occupancy of the ATF6 promoter not shown
    • How feedback is terminated unaddressed
  7. 2011 High

    Connected ATF6 to additional regulatory inputs and target programs: PERK/ATF4 facilitates ATF6 synthesis and ER-to-Golgi trafficking, and BMP2/Runx2 drives ATF6 to induce osteocalcin, expanding ATF6 beyond generic stress.

    Evidence PERK conditional knockout with fractionation; ChIP, promoter reporters, Runx2-/- osteoblasts with dominant-negative ATF6

    PMID:21917591 PMID:22102412

    Open questions at the time
    • Mechanism by which PERK promotes ATF6 trafficking not molecularly defined
    • Whether Runx2 control of ATF6 generalizes beyond bone unknown
  8. 2012 High

    Discovered a second, lipid-sensing activation route, showing ATF6 transmembrane-domain mutations selectively abolish dihydrosphingosine/dihydroceramide activation while sparing proteotoxic activation.

    Evidence Transmembrane motif mutagenesis, lipid addition, and UPR reporter assays

    PMID:30086303

    Open questions at the time
    • How sphingolipids are sensed by the transmembrane domain mechanistically unknown
    • In vivo relevance of lipid-driven ATF6 activation not established
  9. 2014 High

    Identified phosphorylation control of ATF6 processing, showing the ASK1-MKK3/6-p38 axis phosphorylates a threonine required for Golgi cleavage and IFN-γ-driven gene expression and autophagy.

    Evidence Kinase assay, phosphosite mutagenesis, pathway inhibitors, and ASK1-/- mice

    PMID:25135476

    Open questions at the time
    • How phosphorylation enables proteolysis mechanistically unresolved
    • Cross-talk with BiP release not integrated
  10. 2016 High

    Broadened the ATF6 target program to oxidative-stress defense, identifying catalase as a direct ATF6 target whose induction protects the ischemic heart.

    Evidence Gene array, EMSA/ChIP, ATF6 KO mice, AAV9 overexpression, and catalase rescue in I/R

    PMID:27932512

    Open questions at the time
    • Breadth of the ATF6 oxidative-stress regulon beyond catalase undefined
    • Tissue specificity of this program not delineated
  11. 2016 High

    Defined the disease mechanism of ATF6 loss by classifying achromatopsia mutations into trafficking-defective, constitutively active, and transactivation-dead classes with distinct cellular consequences.

    Evidence Functional analysis of patient mutations: trafficking, proteolysis, reporter, and fibroblast death assays

    PMID:28028229

    Open questions at the time
    • Why retinal cones are selectively vulnerable not explained here
    • Whether constitutively active alleles are gain-of-function in vivo unclear
  12. 2018 High

    Established ATF6 abundance as a tunable control point and dissected ATF6-specific proteostasis output: EDEM1 limits ATF6 stability/export, ATF6 acts as a negative off-switch on IRE1, and ATF6 vs XBP1s programs remodel proteostasis differently; selective small molecules (e.g. compound 147) activate ATF6 via ER-localized covalent PDI modification.

    Evidence siRNA stability screens, shRNA silencing with N-terminal rescue, UPR reporters, quantitative proteomics, and chemical proteomics with PDI depletion

    PMID:23583182 PMID:30084354 PMID:30281916 PMID:30287689

    Open questions at the time
    • How ATF6 represses IRE1 transcription mechanistically unresolved
    • Direct ATF6 targets distinguishing it from XBP1s not all mapped
  13. 2018 Medium

    Demonstrated cell-fate and developmental roles for ATF6 across mesoderm specification, TH2/TH17 differentiation, and hepatic fibrinolysis, showing it drives lineage- and tissue-specific transcriptional programs.

    Evidence Patient iPSC and small-molecule agonist differentiation assays; T cell-specific and hepatocyte-specific Atf6 knockouts with in vivo phenotypes

    PMID:29440509 PMID:30504459 PMID:37209959

    Open questions at the time
    • Direct ATF6 target genes in each lineage incompletely defined
    • Whether these roles depend on canonical proteolytic activation untested in some contexts
  14. 2019 High

    Connected ATF6 to growth signaling and apoptotic control, identifying RHEB as a direct cardiac ATF6 target activating mTORC1-driven hypertrophy and showing ATF6 shapes CHOP induction dynamics and cell-fate decisions.

    Evidence Cardiac-specific Atf6 cKO with ChIP and AAV9-RHEB rescue; BAC-GFP reporters, live imaging, and mathematical modeling of UPR branches

    PMID:30582446 PMID:32058971

    Open questions at the time
    • How ATF6 balances pro-survival vs pro-apoptotic outputs unresolved
    • Quantitative contribution of each UPR arm to cell fate not fully apportioned
  15. 2021 High

    Resolved the ubiquitin/proteasome regulation of ATF6, identifying RNF186-mediated K152 ubiquitination downstream of NOD2, OTUB1-mediated deubiquitination/stabilization, and a GRINA-HRD1 degradation complex, defining a regulatory layer controlling ATF6 amount and signaling in immunity, cancer, and organ injury.

    Evidence Site-specific ubiquitination mapping, co-IP/MS complex identification, deubiquitinase assays, and multiple KO/transgenic mouse models

    PMID:33686769 PMID:34623328 PMID:39855351

    Open questions at the time
    • Hierarchy and competition among these ubiquitin enzymes unresolved
    • Whether K152 modification alters trafficking vs stability not fully separated
  16. 2021 High

    Cemented ATF6 as essential for retinal proteostasis and cone development, showing ATF6-null organoids fail cone formation while rods develop, and ATF6 is required to clear misfolded P23H rhodopsin, with agonists rescuing some disease alleles.

    Evidence CRISPR-null hESCs, patient iPSC organoids, Atf6/P23H double mutant mice, patient retinal imaging, and small-molecule agonist rescue

    PMID:34381136 PMID:34561305

    Open questions at the time
    • Why cones uniquely require ATF6 mechanistically unexplained
    • Therapeutic window for agonist rescue in patients undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple activation inputs (BiP release, lipid sensing, p38 phosphorylation) and abundance-control enzymes (RNF186, OTUB1, GRINA-HRD1) are integrated to produce tissue-specific ATF6 transcriptional outputs remains unresolved.
  • No unified model coordinating proteolytic, phosphorylation, and ubiquitin control
  • Determinants of cell-type-specific ATF6 target gene selection unknown
  • Structural basis of ATF6 partner choice (SREBP2, SRF, Runx2) undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 3 GO:0005634 nucleus 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
BIP/HSPA5GRINAOTUB1RNF186RUNX2SREBP2SRFVAPB
Complex memberships
GRINA-HRD1-ATF6 ubiquitination complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ATF6 (a basic-leucine zipper protein) was identified as a direct binding partner of serum response factor (SRF), specifically interacting with SRF's transcriptional activation domain. This interaction was detected by yeast two-hybrid screen and confirmed in vitro. An ATF6-VP16 chimera activated SRE reporter expression, and antisense ATF6 reduced serum induction of c-fos, indicating ATF6 participates in SRF-dependent transcription. Yeast two-hybrid screen, in vitro binding assay, reporter gene assay, antisense inhibition Molecular and cellular biology Medium 9271374
2000 ATF6 binds a consensus DNA sequence related to but distinct from ATF1/CREB sites; this ATF6-binding site is specifically activated by ATF6 overexpression and strongly induced by ER stress. A dominant-negative ATF6 blocked ER stress induction of both ATF6-site and GRP78 reporter genes. GAL4-ATF6 was activated by ER stress, demonstrating ATF6 is a direct transcriptional effector of the ER stress response. Human IRE1 (hIRE1) was found sufficient to activate the ATF6 reporter, and dominant-negative hIRE1 blocked it, placing hIRE1 upstream of ATF6. Reporter gene assay, dominant-negative constructs, GAL4 fusion assay, transient transfection The Journal of biological chemistry High 10856300
2001 ATF6 was shown to transcriptionally induce XBP1, and only the IRE1-spliced form of XBP1 mRNA produces a highly active transcription factor that efficiently activates the UPR. ATF6-dependent and IRE1-dependent pathways were thus linked, with ATF6 functioning upstream of XBP1 induction. Transcriptional reporter assays, Northern/Western blotting, identification of spliced XBP1 product Cell High 11779464
2002 ATF6's N-terminal 93 amino acids contain a domain homologous to the VP16 viral protein (VN8 region) that is simultaneously required for transcriptional activation and rapid proteasomal degradation. Point mutations in this VN8-like domain caused loss of transcriptional activity, increased ATF6 expression levels, and increased half-life, demonstrating that potent transcriptional activity and rapid proteasome-mediated turnover of ATF6 are co-regulated by this domain. Deletion and point mutagenesis, reporter gene assay, proteasome inhibitor treatment, protein half-life measurement The Journal of biological chemistry High 11909875
2002 The ER chaperone BiP/GRP78 binds ATF6 and retains it in the ER; dissociation of BiP from ATF6 upon ER stress initiates ATF6 transport to the Golgi for proteolytic activation. BiP thus acts as a key sensor of ER folding capacity controlling ATF6 activation. Review/commentary citing experimental evidence from same issue (co-immunoprecipitation and trafficking assays described in referenced primary paper) Developmental cell Medium 12110159
2004 ATF6's N-terminal fragment (ATF6(N)) directly binds SREBP2(N) via its leucine-zipper domain, as shown by GST pull-down and co-immunoprecipitation. ATF6(N) forms a complex with SREBP2(N) on sterol response elements (ChIP assay) and recruits HDAC1 to this complex, thereby attenuating SREBP2-mediated lipogenic transcription. Glucose deprivation activates ATF6 and suppresses SREBP2 target genes, and blocking ATF6 cleavage (by BiP overexpression) reverses this inhibitory effect. GST pull-down, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter gene assay, deletion analysis The EMBO journal High 14765107
2007 ER stressors transcriptionally upregulate ATF6 mRNA expression. This upregulation is mediated by proteolytically cleaved p50-ATF6 binding to putative ATF6-binding elements in the ATF6 promoter, creating a positive autoregulatory feedback loop. Inhibition of S1P (the protease that cleaves ATF6) suppressed ATF6 mRNA upregulation. RT-PCR, promoter reporter assay, S1P inhibitor treatment Biochemical and biophysical research communications Medium 17307147
2008 VAPA and VAPB MSP domains interact directly with ER-localized ATF6. Overexpression of VAPB or the ALS-associated mutant VAPB(P56S) attenuates ATF6-regulated transcriptional activity, with the P56S mutant being a more potent inhibitor of ATF6 activity. Co-immunoprecipitation, transcriptional reporter assay, overexpression studies Human molecular genetics Medium 18263603
2009 Simulated ischemia (sI) in cardiac myocytes causes ATF6 to translocate from the ER to nuclear fractions. An ERSE in the GRP78 promoter not previously required for other ER stresses was found to bind ATF6 and was critical for maximal ischemia-mediated GRP78 induction. Dominant-negative ATF6 or ATF6-targeted miRNA blocked sI-mediated GRP78 induction and increased cardiac myocyte death upon reperfusion, establishing ATF6 as the key mediator of the ischemic ER stress response. Subcellular fractionation, ChIP/EMSA, dominant-negative ATF6, miRNA knockdown, cell death assay The Journal of biological chemistry High 19622751
2011 BMP2 induces ATF6 expression and activation in osteoblasts through Runx2 directly binding to an OSE2 motif (-205 to -200 bp) in the Atf6 promoter. ATF6 in turn directly binds an ATF6-binding motif in the osteocalcin (Oc) promoter to induce Oc expression. Dominant-negative ATF6 blocked BMP2/Runx2-induced osteocalcin expression, and BMP2-induced ATF6 activation was absent in Runx2-/- osteoblasts. ChIP assay, promoter reporter assay, dominant-negative ATF6, Runx2-/- cells, overexpression The Journal of biological chemistry High 22102412
2011 The PERK/eIF2α~P/ATF4 pathway is required not only for translational control but also for activation of ATF6 and its target genes during ER stress. PERK facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis. Liver-specific PERK depletion significantly reduces ATF6 activation. Genetic knockdown/knockout of PERK, immunoblot, subcellular fractionation, liver-specific conditional knockout Molecular biology of the cell High 21917591
2012 ATF6 possesses two mechanistically distinct activation pathways: (1) a luminal domain-dependent pathway activated by proteotoxic/ER stress, and (2) a transmembrane domain-dependent pathway activated by specific sphingolipids dihydrosphingosine (DHS) and dihydroceramide (DHC). Single point mutations in a newly identified transmembrane domain motif selectively abolish DHS/DHC-mediated activation while leaving proteotoxic stress activation intact. Site-directed mutagenesis, lipid addition assays, UPR reporter assays, pharmacological induction Developmental cell High 30086303
2013 ATF6 directly binds the XBP1 promoter to enhance XBP1 expression; both ATF6 and IRE1α synergistically regulate endogenous XBP1S gene expression in osteoarthritis cartilage. siRNA knockdown experiments confirmed ATF6's role upstream of XBP1S. ChIP assay, siRNA knockdown, promoter analysis, Western blotting Cellular signalling Medium 24269637
2014 The ASK1-MKK3/MKK6-p38 MAPK pathway controls ATF6 activity downstream of IFN-γ signaling. p38 MAPK phosphorylates a critical threonine residue in ATF6 upstream of its DNA binding domain. ATF6 mutants defective for p38 MAPK phosphorylation fail to undergo proteolytic processing in the Golgi and cannot drive IFN-γ-induced gene expression or autophagy. Kinase assay (p38 MAPK phosphorylation), site-directed mutagenesis, pharmacological inhibition of ASK1/MKK/p38, reporter assay, ASK1-/- mice Molecular and cellular biology High 25135476
2016 ATF6 induces a program of oxidative stress response genes (including catalase) in addition to canonical ER chaperone genes. ER stress response elements (ERSEs) were identified in the catalase gene promoter and shown to bind ATF6 in cardiac myocytes, increasing catalase promoter activity. ATF6 knockout hearts showed increased ROS and damage after ischemia/reperfusion that was rescued by catalase overexpression, establishing catalase as a functional ATF6 target linking ER and oxidative stress responses. Gene array, EMSA/ChIP (ERSE-ATF6 binding), ATF6 KO mice, AAV9-mediated ATF6 overexpression, catalase overexpression rescue, I/R model Circulation research High 27932512
2016 Achromatopsia-associated ATF6 mutations fall into three mechanistic classes: Class 1 — impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity; Class 2 — intact cytosolic domain with constitutive transcriptional activity even without ER stress; Class 3 — complete loss of transcriptional activity due to absent or defective bZIP domains. Patient fibroblasts with Class 1 or Class 3 mutations show increased cell death in response to ER stress. Functional ATF6 mutation analysis, subcellular trafficking assays, proteolytic processing assays, transcriptional reporter assays, patient fibroblast cell death assays Proceedings of the National Academy of Sciences of the United States of America High 28028229
2018 The small molecule 147 (N-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide) preferentially activates ATF6 through metabolic oxidation to an electrophile that covalently modifies ER-resident proteins including protein disulfide isomerases (PDIs). Genetic depletion of PDIs perturbs 147-dependent induction of the ATF6 target gene BiP, implicating PDI modification in ATF6-selective activation. Thus 147 functions as a pro-drug that activates ATF6 via localized ER-targeted covalent modification. Chemical proteomics (identification of covalently modified proteins), genetic PDI depletion, target gene induction assay, metabolic activation studies eLife High 30084354
2018 Loss of ATF6 expression results in uncontrolled IRE1 signaling and increased XBP1 splicing. The transcriptionally active N-terminal domain of ATF6 reversed increases in IRE1 mRNA and protein levels induced by ER stress, establishing ATF6 as a negative regulator ('off-switch') of IRE1 signaling. IRE1 transcription is regulated through a positive feed-forward loop involving IRE1 kinase activity and downstream JNK. shRNA-mediated ATF6 silencing, live-cell fluorescent UPR reporter assay, IRE1 overexpression with ATF6-N-terminal domain rescue, JNK/IRE1 kinase inhibition The Journal of biological chemistry High 30287689
2018 ATF6 is required for EDEM1-regulated ER export; silencing EDEM1 increases ATF6 bioavailability by stabilizing the natively unstable ATF6 protein, enhancing its export to the Golgi for S1P/S2P cleavage. A somatic EDEM1 variant (N198I) found in hepatocellular carcinoma alters ATF6 signaling. siRNA phenotypic screen, ATF6 stability assays, EDEM1 silencing and variant analysis The FEBS journal Medium 30281916
2018 ATF6 is induced by STAT6 in TH2 cells and STAT3 in TH17 cells, and ATF6 promotes TH2 and TH17 differentiation and cytokine secretion. T cell-specific Atf6 deficiency impaired TH2 and TH17 responses in vitro and in vivo and attenuated mixed granulocytic experimental asthma. Conditional T cell-specific Atf6 knockout mice, in vitro differentiation assays, cytokine measurement, in vivo asthma model Mucosal immunology Medium 37209959
2018 ATF6 promotes mesodermal cell fate during differentiation of human stem cells. Pharmacological ATF6 activation suppressed pluripotency and directed mesodermal differentiation; conversely, iPSCs from patients with ATF6 loss-of-function mutations showed impaired mesodermal differentiation. Small-molecule ATF6 agonist activation, patient iPSC lines with ATF6 mutations, transcriptome analysis of germ layer markers Science signaling Medium 29440509
2018 ATF6 induces the tPA gene (Plat) in hepatocytes; the co-repressor DACH1 represses ATF6, thereby reducing hepatocyte Plat expression and circulating tPA. Hepatocyte-ATF6 knockout mice show decreased plasma tPA, fibrinolytic activity, and altered thrombosis parameters, establishing a DACH1-ATF6-tPA axis controlling systemic fibrinolysis. Hepatocyte-specific ATF6 knockout mice, DACH1 knockout mice, hepatocyte Plat silencing, measurement of plasma tPA and fibrinolytic activity Blood High 30504459
2019 ATF6 transcriptionally induces RHEB (Ras homologue enriched in brain), an activator of mTORC1, during cardiac hypertrophy. Cardiac myocyte-specific ATF6 deletion blunted hypertrophy and mTORC1 activation in response to pressure overload and exercise; ectopic RHEB expression restored hypertrophy in ATF6 cKO hearts. ChIP identified RHEB as a direct ATF6 target gene in the heart. Cardiac myocyte-specific Atf6 conditional knockout, transcript profiling, ChIP, AAV9-RHEB rescue, transverse aortic constriction and exercise models Circulation research High 30582446
2020 ATF6 shapes the early dynamics of pro-apoptotic CHOP during the UPR. Mathematical modeling and siRNA knockdown of individual UPR branches showed that ATF6 is required for full CHOP induction dynamics, with ATF6 acting as an important regulator of CHOP and therefore cell fate decisions. BAC-GFP reporter cell lines, live-cell microscopy, dynamic mathematical modeling, single siRNA knockdowns iScience Medium 32058971
2020 In C. elegans, inhibition of the ATF6 ortholog (atf-6) increases lifespan by modulating calcium homeostasis: atf-6 loss downregulates the ER calcium buffer calreticulin, and ER calcium release via IP3R (itr-1) is required for longevity. Mitochondrial calcium import channel mcu-1 is also required for the longevity conferred by atf-6 loss, revealing an ER-mitochondria calcium signaling axis downstream of atf-6. C. elegans genetic loss-of-function, epistasis analysis with itr-1 (IP3R) and mcu-1 mutants, lifespan assays, calcium flux measurements Cell reports Medium 32905769
2020 ATF6 decreases the activation of cardiac fibroblasts in response to TGFβ by suppressing fibroblast contraction and α-smooth muscle actin (αSMA) induction through inhibition of the TGFβ-Smad signaling axis. ATF6 silencing or deletion hyperactivated fibroblasts. ATF6 activation (pharmacological), siRNA knockdown, ATF6 knockout fibroblasts, contraction assay, αSMA measurement International journal of molecular sciences Medium 32085622
2021 RNF186, an E3 ubiquitin ligase, ubiquitinates ATF6 at lysine 152 upon NOD2 pattern recognition receptor stimulation in human macrophages. RNF186 localizes to the ER and forms a complex with ER stress sensors including ATF6; this ubiquitination promotes UPR activation, cytokine secretion, and antimicrobial pathway induction. IBD-associated RNF186 risk variants reduce NOD2-induced ATF6 ubiquitination and downstream outcomes. Co-immunoprecipitation, ubiquitination assay with K152 mutagenesis, RNF186-deficient cells, ATF6-deficient mice, in vivo infection models The Journal of clinical investigation High 34623328
2021 OTUB1 (deubiquitinase otubain 1) stabilizes ATF6 by inhibiting its ubiquitylation in response to ER stress, thereby activating ATF6 signaling and promoting bladder cancer progression. Genetic ablation of OTUB1 inhibited ATF6 target gene expression and cancer cell proliferation. Luciferase pathway screening, OTUB1 knockout (in vitro and in vivo), ubiquitylation assay Cancer science Medium 33686769
2021 ATF6 is essential for human cone photoreceptor development. Retinal organoids from ATF6-null hESCs or achromatopsia patient iPSCs failed to form cone structures and lost cone phototransduction gene expression, while rod photoreceptors developed normally. A selective small-molecule ATF6 agonist restored transcriptional activity of some ATF6 disease variants and stimulated cone growth in patient organoids. CRISPR/Cas9 ATF6 null hESCs, patient iPSC retinal organoids, gene expression analysis, adaptive optics retinal imaging of patients, small-molecule ATF6 agonist rescue Proceedings of the National Academy of Sciences of the United States of America High 34561305
2021 ATF6 is required for efficient clearance of P23H mutant rhodopsin in rod photoreceptors. Atf6-/- mice expressing P23H rhodopsin accumulate more rhodopsin protein at early ages (without changes in mRNA), and ultimately develop accelerated retinal degeneration compared to Atf6+/- controls. Atf6 knockout combined with P23H rhodopsin knock-in, rhodopsin protein and mRNA quantification, retinal layer thickness measurement Scientific reports Medium 34381136
2021 ATF6 directly binds the promoter of p53 and AIFM2 to promote their transcription in severe acute pancreatitis (SAP). ATF6 knockout in SAP mice attenuated acinar injury and apoptosis; AIFM2 overexpression re-established pathological disorder in ATF6-KO SAP mice. p53 knockout significantly suppressed acinar apoptosis and injury. ATF6 knockout mice, ChIP-qPCR, luciferase reporter assay, adenovirus-mediated overexpression/knockdown, proteomics Theranostics Medium 32724472
2025 GRINA interacts directly with ATF6 and recruits HRD1 to form a multiprotein complex that catalyzes ATF6 polyubiquitination, promoting ATF6 degradation. This GRINA-HRD1-ATF6 complex suppresses ER autophagy (ER-phagy) and protects hepatocytes from ischemia-reperfusion injury. Inhibition of ATF6 degradation attenuated the protective effects of GRINA. Co-immunoprecipitation, mass spectrometry, ubiquitination assay, hepatocyte-specific Grina KO and transgenic mice, RNA sequencing Journal of hepatology High 39855351
2015 ATF6a interacts directly with Runx2 protein and augments Runx2-mediated hypertrophic chondrocyte differentiation. Overexpression of ATF6/ATF6a enhanced chondrogenesis and mineralization; ATF6a knockdown suppressed chondrocyte differentiation. ATF6a also regulated IHH and PTHrP signaling during chondrocyte hypertrophy. Co-immunoprecipitation (ATF6a-Runx2 interaction), siRNA knockdown, adenoviral overexpression, in vitro differentiation assay, immunohistochemistry Journal of cell science Medium 26527399
2020 BCAA/BCKA (branched chain amino acids and keto acids, specifically valine and leucine but not isoleucine) transcriptionally upregulate PPAR-α through the GCN2/ATF6 pathway. In a genetic mouse model with BCAA catabolic defects, adenovirus-mediated PPAR-α silencing reversed the increased fatty acid oxidation and cardiac I/R vulnerability caused by BCAA accumulation. Seahorse metabolic flux analysis, BCAA oral gavage mouse model, genetic BCAA catabolic defect model, adenovirus-mediated PPAR-α silencing Theranostics Medium 32373236
2018 ATF6 transcriptional programs (activated independently of stress using a small molecule) remodel the ER proteostasis network in ways that are distinct from XBP1s programs and differentially influence folding, trafficking, and degradation of destabilized ER client proteins. Quantitative proteomics defined the specific proteostasis factors upregulated by ATF6 versus XBP1s. Orthogonal small-molecule-mediated ATF6/XBP1s activation, transcriptomics, quantitative proteomics Cell reports Medium 23583182

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 3335 11779464
2000 Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. The Journal of biological chemistry 484 10856300
2013 Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell reports 465 23583182
2011 The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Molecular biology of the cell 334 21917591
2016 ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart. Circulation research 270 27932512
2018 A lifetime of stress: ATF6 in development and homeostasis. Journal of biomedical science 217 29801500
2015 Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nature genetics 183 26029869
2004 ATF6 modulates SREBP2-mediated lipogenesis. The EMBO journal 182 14765107
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 169 23011799
2011 BMP2 protein regulates osteocalcin expression via Runx2-mediated Atf6 gene transcription. The Journal of biological chemistry 166 22102412
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 146 30086303
2008 VAPB interacts with and modulates the activity of ATF6. Human molecular genetics 138 18263603
2009 Ischemia activates the ATF6 branch of the endoplasmic reticulum stress response. The Journal of biological chemistry 136 19622751
2014 Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression. Autophagy 130 24589849
2020 Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation. Theranostics 120 32373236
2019 ATF6 Regulates Cardiac Hypertrophy by Transcriptional Induction of the mTORC1 Activator, Rheb. Circulation research 102 30582446
2020 ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response. iScience 100 32058971
2018 ER stress signaling has an activating transcription factor 6α (ATF6)-dependent "off-switch". The Journal of biological chemistry 100 30287689
2018 Activated ATF6 Induces Intestinal Dysbiosis and Innate Immune Response to Promote Colorectal Tumorigenesis. Gastroenterology 99 30063920
2012 The ATF6 branch of unfolded protein response and apoptosis are activated to promote African swine fever virus infection. Cell death & disease 99 22764100
2018 Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins. eLife 95 30084354
2019 Expression of UPR effector proteins ATF6 and XBP1 reduce colorectal cancer cell proliferation and stemness by activating PERK signaling. Cell death & disease 91 31227689
2013 ATF6 upregulates XBP1S and inhibits ER stress-mediated apoptosis in osteoarthritis cartilage. Cellular signalling 87 24269637
2013 Sustained IRE1 and ATF6 signaling is important for survival of melanoma cells undergoing ER stress. Cellular signalling 80 24240056
2018 miR-103/107 promote ER stress-mediated apoptosis via targeting the Wnt3a/β-catenin/ATF6 pathway in preadipocytes. Journal of lipid research 79 29483204
2018 ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells. Journal of neuroinflammation 79 30241539
2020 ID1 confers cancer cell chemoresistance through STAT3/ATF6-mediated induction of autophagy. Cell death & disease 78 32080166
2020 ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis. Theranostics 78 32724472
2019 Proteostasis and Beyond: ATF6 in Ischemic Disease. Trends in molecular medicine 76 31078432
2024 Molecular mechanism of ATF6 in unfolded protein response and its role in disease. Heliyon 75 38434326
2018 ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells. Cell discovery 73 29423270
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 67 24140798
2020 Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis. Cell reports 66 32905769
2015 Mutation of ATF6 causes autosomal recessive achromatopsia. Human genetics 66 26063662
2002 BiP binding keeps ATF6 at bay. Developmental cell 64 12110159
2014 Regulation of the death-associated protein kinase 1 expression and autophagy via ATF6 requires apoptosis signal-regulating kinase 1. Molecular and cellular biology 63 25135476
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
2022 Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes. Nature communications 56 36216837
2018 The unfolded protein response regulator ATF6 promotes mesodermal differentiation. Science signaling 55 29440509
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
2019 Characterization of Retinal Structure in ATF6-Associated Achromatopsia. Investigative ophthalmology & visual science 49 31237654
2016 Achromatopsia mutations target sequential steps of ATF6 activation. Proceedings of the National Academy of Sciences of the United States of America 47 28028229
2021 ATF6 is essential for human cone photoreceptor development. Proceedings of the National Academy of Sciences of the United States of America 46 34561305
2019 Seneca valley virus activates autophagy through the PERK and ATF6 UPR pathways. Virology 46 31539773
2020 Intersection of the ATF6 and XBP1 ER stress pathways in mouse islet cells. The Journal of biological chemistry 45 32788214
2009 Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway. The Biochemical journal 45 18840095
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 43 37658050
2022 ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress. Cell death discovery 43 35752616
2007 Transcriptional activation of ATF6 by endoplasmic reticulum stressors. Biochemical and biophysical research communications 41 17307147
2021 p62-Induced Cancer-Associated Fibroblast Activation via the Nrf2-ATF6 Pathway Promotes Lung Tumorigenesis. Cancers 39 33670717
2020 ATF6 as a Nodal Regulator of Proteostasis in the Heart. Frontiers in physiology 37 32322217
2018 Alterations of EDEM1 functions enhance ATF6 pro-survival signaling. The FEBS journal 36 30281916
2021 OTUB1 facilitates bladder cancer progression by stabilizing ATF6 in response to endoplasmic reticulum stress. Cancer science 35 33686769
2021 ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model. Scientific reports 33 34381136
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
2018 ER Stress Activates the TOR Pathway through Atf6. Journal of molecular signaling 32 30210580
2021 Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response. The Journal of clinical investigation 31 34623328
2018 An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1. Blood 30 30504459
2022 Gremlin-1 Promotes Colorectal Cancer Cell Metastasis by Activating ATF6 and Inhibiting ATF4 Pathways. Cells 29 35883579
2020 The role of ATF6 in Cr(VI)-induced apoptosis in DF-1 cells. Journal of hazardous materials 27 33243643
2019 ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis. Cell death & disease 27 31506423
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
2023 ATF6-Mediated Signaling Contributes to PARP Inhibitor Resistance in Ovarian Cancer. Molecular cancer research : MCR 25 36149636
2022 Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors. Cell & bioscience 25 35477478
2021 IL-6/STAT3 Induced Neuron Apoptosis in Hypoxia by Downregulating ATF6 Expression. Frontiers in physiology 25 34744770
2020 The ATF6-EGF Pathway Mediates the Awakening of Slow-Cycling Chemoresistant Cells and Tumor Recurrence by Stimulating Tumor Angiogenesis. Cancers 25 32630838
2018 Pharmacologic inhibition of S1P attenuates ATF6 expression, causes ER stress and contributes to apoptotic cell death. Toxicology and applied pharmacology 25 29689241
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 ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy-Dependent Pathway. Frontiers in immunology 24 33679742
2020 The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts. International journal of molecular sciences 24 32085622
2019 Psoralen induces hepatic toxicity through PERK and ATF6 related ER stress pathways in HepG2 cells. Toxicology mechanisms and methods 23 31364909
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
2025 Embelin improves alcoholic steatohepatitis in alcohol-associated liver disease via ATF6-mediated P2X7r-NLRP3 signaling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 21 40106966
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
2009 The ATF6-Met[67]Val substitution is associated with increased plasma cholesterol levels. Arteriosclerosis, thrombosis, and vascular biology 21 19667116
2015 ATF6a, a Runx2-activable transcription factor, is a new regulator of chondrocyte hypertrophy. Journal of cell science 20 26527399
2023 Protocadherin 20 maintains intestinal barrier function to protect against Crohn's disease by targeting ATF6. Genome biology 19 37407995
2020 Multiexon deletion alleles of ATF6 linked to achromatopsia. JCI insight 19 32271167
2022 Peste des Petits Ruminants Virus Upregulates STING to Activate ATF6-Mediated Autophagy. Journal of virology 17 36197111
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
2023 Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis. Cell chemical biology 16 36630963
2023 Unfolded protein response factor ATF6 augments T helper cell responses and promotes mixed granulocytic airway inflammation. Mucosal immunology 16 37209959
2023 The role of GRP78/ATF6/IRE1 and caspase-3/Bax/Bcl2 signaling pathways in the protective effects of gallic acid against cadmium-induced liver damage in rats. Iranian journal of basic medical sciences 16 37886005
2015 Mineral trioxide aggregate induces osteoblastogenesis via Atf6. Bone reports 16 28377952
2022 Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway. Neuropathology and applied neurobiology 15 35338505
2015 ATF6 pathway of unfolded protein response mediates advanced oxidation protein product-induced hypertrophy and epithelial-to-mesenchymal transition in HK-2 cells. Molecular and cellular biochemistry 15 26045172
2025 GRINA alleviates hepatic ischemia‒reperfusion injury-induced apoptosis and ER-phagy by enhancing HRD1-mediated ATF6 ubiquitination. Journal of hepatology 14 39855351
2025 Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis. Nature communications 14 39905002
2024 Curcumin affects apoptosis of colorectal cancer cells through ATF6-mediated endoplasmic reticulum stress. Chemical biology & drug design 14 38230779
2023 PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6. iScience 14 36824269
2022 Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling. Cell death discovery 14 35289326
2019 The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes. Aging 14 31061237

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