activating transcription factor 6


Summary: One of the BASIC-LEUCINE ZIPPER TRANSCRIPTION FACTORS that is synthesized as a membrane-bound protein in the ENDOPLASMIC RETICULUM. In response to endoplasmic reticulum stress it translocates to the GOLGI APPARATUS. It is activated by PROTEASES and then moves to the CELL NUCLEUS to regulate GENETIC TRANSCRIPTION of GENES involved in the unfolded protein response.

Top Publications

  1. Seo H, Kim M, Min A, Kim H, Ryu S, Kim N, et al. Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases cAMP-stimulated hepatic gluconeogenesis via inhibition of CREB. Endocrinology. 2010;151:561-8 pubmed publisher
    ..whether ER stress influences hepatic gluconeogenesis and whether this process is mediated by activating transcription factor 6 (ATF6) through the inhibition of cAMP-mediated activation of CREB...
  2. Oslowski C, Urano F. Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol. 2011;490:71-92 pubmed publisher
    ..These methods will assist us in understanding the UPR and its contribution to ER stress-related disorders such as diabetes and neurodegeneration. ..
  3. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081-6 pubmed publisher
    ..Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases. ..
  4. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell. 1999;10:3787-99 pubmed
    ..Unlike yeast UPR, mammalian UPR appears to use a system similar to that reported for cholesterol homeostasis. ..
  5. Thameem F, Farook V, Bogardus C, Prochazka M. Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes. 2006;55:839-42 pubmed
    b>Activating transcription factor 6 (ATF6) is important for protective cell response to accumulation of unfolded and misfolded proteins in endoplasmic reticulum, and disturbances of this process can contribute to beta-cell apoptosis...
  6. Shen J, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell. 2002;3:99-111 pubmed
    ..These results suggest that BiP retains ATF6 in the ER by inhibiting its GLSs and that dissociation of BiP during ER stress allows ATF6 to be transported to the Golgi. ..
  7. Shkoda A, Ruiz P, Daniel H, Kim S, Rogler G, Sartor R, et al. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology. 2007;132:190-207 pubmed
    ..IL-10 inhibits inflammation-induced ER stress response mechanisms by modulating ATF-6 nuclear recruitment to the grp-78 gene promoter. ..
  8. Hai T, Hartman M. The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene. 2001;273:1-11 pubmed
    ..Despite the diversity in the potential functions of these proteins, one common theme is their involvement in cellular responses to extracellular signals, indicating a role for these ATF proteins in homeostasis. ..
  9. Haze K, Okada T, Yoshida H, Yanagi H, Yura T, Negishi M, et al. Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response. Biochem J. 2001;355:19-28 pubmed
    ..We thus concluded that the two related bZIP proteins are crucial transcriptional regulators of the mammalian UPR, and propose calling the ATF6 gene product ATF6alpha and the G13 gene product ATF6beta. ..

More Information


  1. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol. 2000;20:6755-67 pubmed
    ..Based on these and other findings, we concluded that specific and direct interactions between ATF6 and ERSE are critical for transcriptional induction not only of ER chaperones but also of CHOP and XBP-1. ..
  2. Shen J, Snapp E, Lippincott Schwartz J, Prywes R. Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response. Mol Cell Biol. 2005;25:921-32 pubmed
    ..We propose that stable BiP binding is essential for ATF6 regulation and that ER stress dissociates BiP from ATF6 by actively restarting the BiP ATPase cycle. ..
  3. Senkal C, Ponnusamy S, Manevich Y, Meyers Needham M, Saddoughi S, Mukhopadyay A, et al. Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network. J Biol Chem. 2011;286:42446-58 pubmed publisher
    ..Overall, these data suggest a novel mechanism of how CerS6/C(16)-ceramide alteration activates ATF6 and induces ER-stress-mediated apoptosis in squamous cell carcinomas. ..
  4. Wu J, Rutkowski D, Dubois M, Swathirajan J, Saunders T, Wang J, et al. ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell. 2007;13:351-64 pubmed
    ..These results suggest that the vertebrate ATF6alpha pathway evolved to maintain ER function when cells are challenged with chronic stress and provide a rationale for the overlap among the three UPR pathways. ..
  5. Chin K, Zhou H, Wong C, Lee J, Chan C, Qiang B, et al. The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma. Nucleic Acids Res. 2005;33:1859-73 pubmed
    ..Taken together, our findings suggest that the liver-enriched bZIP transcription factor CREB-H is a growth suppressor that plays a role in hepatic physiology and pathology. ..
  6. van Huizen R, Martindale J, Gorospe M, Holbrook N. P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. J Biol Chem. 2003;278:15558-64 pubmed
    ..These findings implicate P58(IPK) as an important component of a negative feedback loop used by the cell to inhibit eIF2alpha signaling, and thus attenuate the unfolded protein response. ..
  7. Nadanaka S, Yoshida H, Kano F, Murata M, Mori K. Activation of mammalian unfolded protein response is compatible with the quality control system operating in the endoplasmic reticulum. Mol Biol Cell. 2004;15:2537-48 pubmed
  8. Li S, Ye L, Yu X, Xu B, Li K, Zhu X, et al. Hepatitis C virus NS4B induces unfolded protein response and endoplasmic reticulum overload response-dependent NF-kappaB activation. Virology. 2009;391:257-64 pubmed publisher
    ..These studies provide an important insight into the implication of NS4B in HCV life cycle and HCV-associated liver disease by affecting host intracellular signal transduction pathways. ..
  9. Hirota M, Kitagaki M, Itagaki H, Aiba S. Quantitative measurement of spliced XBP1 mRNA as an indicator of endoplasmic reticulum stress. J Toxicol Sci. 2006;31:149-56 pubmed
    ..A good correlation was found between spliced XBP1 expression and BiP expression. Thus, our method may be useful for simple and quantitative evaluation of ER stress. ..
  10. Zeng L, Lu M, Mori K, Luo S, Lee A, Zhu Y, et al. ATF6 modulates SREBP2-mediated lipogenesis. EMBO J. 2004;23:950-8 pubmed
    b>Activating transcription factor 6 (ATF6) and sterol regulatory element-binding proteins (SREBPs) are activated by proteolytic cleavage. The ensuing nuclear translocation of their N-termini (i.e...
  11. Seo H, Kim Y, Lee K, Min A, Kim M, Kim H, et al. Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases insulin gene expression via up-regulation of orphan nuclear receptor small heterodimer partner. Endocrinology. 2008;149:3832-41 pubmed publisher
    ..Collectively, this study shows that ER stress-induced activation of ATF6 plays an important role in the development of beta-cell dysfunction...
  12. Kaufman R. Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002;110:1389-98 pubmed
  13. Cinaroglu A, Gao C, Imrie D, Sadler K. Activating transcription factor 6 plays protective and pathological roles in steatosis due to endoplasmic reticulum stress in zebrafish. Hepatology. 2011;54:495-508 pubmed publisher PRKR-like endoplasmic reticulum kinase, inositol-requiring 1A/X box binding protein 1, and activating transcription factor 6 (ATF6), and each of these pathways has been implicated to have a protective or pathological role in ..
  14. Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct. 2008;33:75-89 pubmed
    ..Based on these results, we propose that ATF6 is a transcription factor specialized in the regulation of ER quality control proteins. ..
  15. Medigeshi G, Lancaster A, Hirsch A, Briese T, Lipkin W, DeFilippis V, et al. West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis. J Virol. 2007;81:10849-60 pubmed
    ..inositol-requiring enzyme 1-dependent splicing of X box binding protein 1 (XBP1) mRNA, activation of activating transcription factor 6 (ATF6), and protein kinase R-like endoplasmic reticulum (ER) kinase-dependent eukaryotic initiation ..
  16. Lee A, Iwakoshi N, Glimcher L. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003;23:7448-59 pubmed
    ..Further, our observations suggest the existence of additional, as-yet-unknown, key regulators of the UPR. ..
  17. Thomas M, Yu Z, Dadgar N, Varambally S, Yu J, Chinnaiyan A, et al. The unfolded protein response modulates toxicity of the expanded glutamine androgen receptor. J Biol Chem. 2005;280:21264-71 pubmed
    ..evaluate the role of the UPR, we examined the contributions of three proximal sensors of ER stress: activating transcription factor 6 (ATF6), inositol requiring 1 (IRE1), and PKR-like endoplasmic reticulum kinase (PERK)...
  18. Ye J, Rawson R, Komuro R, Chen X, Dav U, Prywes R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000;6:1355-64 pubmed
    ..ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis...
  19. Nozaki J, Kubota H, Yoshida H, Naitoh M, Goji J, Yoshinaga T, et al. The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2+/Akita pancreatic beta cells. Genes Cells. 2004;9:261-70 pubmed
    ..These results indicate that this cell line is subject to continuous ER stress and that the Ins2 C96Y mutation induces the expression of ER chaperones through the activation of ATF6 and XBP1. ..
  20. Okada T, Haze K, Nadanaka S, Yoshida H, Seidah N, Hirano Y, et al. A serine protease inhibitor prevents endoplasmic reticulum stress-induced cleavage but not transport of the membrane-bound transcription factor ATF6. J Biol Chem. 2003;278:31024-32 pubmed
    ..These results indicate that the transport of ATF6 from the ER to the Golgi apparatus and that from the Golgi apparatus to the nucleus are distinct steps that can be distinguished by treatment with AEBSF. ..
  21. Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 2002;16:452-66 pubmed
    ..Both processing of ATF6 and IRE1alpha-mediated splicing of XBP1 mRNA are required for full activation of the UPR. ..
  22. Zhang K, Kaufman R. Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem. 2004;279:25935-8 pubmed
  23. Nadanaka S, Okada T, Yoshida H, Mori K. Role of disulfide bridges formed in the luminal domain of ATF6 in sensing endoplasmic reticulum stress. Mol Cell Biol. 2007;27:1027-43 pubmed
    ..This mechanism ensures the strictness of regulation, in that the cell can only process ATF6 which has experienced the changes in the ER. ..
  24. Smith S, Granell S, Salcedo Sicilia L, Baldini G, Egea G, Teckman J, et al. Activating transcription factor 6 limits intracellular accumulation of mutant ?(1)-antitrypsin Z and mitochondrial damage in hepatoma cells. J Biol Chem. 2011;286:41563-77 pubmed publisher
    ..Activation of the activating transcription factor 6 (ATF6) branch of the UPR by expression of spliced ATF6(1-373) decreased intracellular accumulation ..
  25. Umareddy I, Pluquet O, Wang Q, Vasudevan S, Chevet E, Gu F. Dengue virus serotype infection specifies the activation of the unfolded protein response. Virol J. 2007;4:91 pubmed
    ..Furthermore, modulators of UPR such as Salubrinal that inhibit Dengue replication may open up an avenue toward cell-protective agents that target the endoplasmic reticulum for anti-viral therapy. ..
  26. Zhu C, Johansen F, Prywes R. Interaction of ATF6 and serum response factor. Mol Cell Biol. 1997;17:4957-66 pubmed
    ..ATF6 was previously partially cloned as a member of the ATF family. The complete cDNA of ATF6 was isolated, and its expression pattern was described. ..
  27. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, et al. Endoplasmic reticulum stress-induced formation of transcription factor complex ERSF including NF-Y (CBF) and activating transcription factors 6alpha and 6beta that activates the mammalian unfolded protein response. Mol Cell Biol. 2001;21:1239-48 pubmed
    ..We concluded that ATF6 homo- or heterodimers recognize and bind directly to both the DNA and adjacent protein NF-Y and that this complex formation process is essential for transcriptional induction of ER chaperones. ..
  28. Kudo T, Kanemoto S, Hara H, Morimoto N, Morihara T, Kimura R, et al. A molecular chaperone inducer protects neurons from ER stress. Cell Death Differ. 2008;15:364-75 pubmed
    ..mediated by activation of ER stress response elements upstream of the BiP gene, through the ATF6 (activating transcription factor 6) pathway. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress...
  29. Yamamoto K, Takahara K, Oyadomari S, Okada T, Sato T, Harada A, et al. Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol Biol Cell. 2010;21:2975-86 pubmed publisher
    ..Accordingly, the hepatocytes of tunicamycin-injected knockout mice were filled with many lipid droplets. These results establish links among ER stress, lipid metabolism, and steatosis. ..
  30. Cunha D, Hekerman P, Ladriere L, Bazarra Castro A, Ortis F, Wakeham M, et al. Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J Cell Sci. 2008;121:2308-18 pubmed publisher
    ..In conclusion, saturated FFA induce ER stress via ER Ca(2+) depletion. The IRE1 and resulting JNK activation contribute to beta-cell apoptosis. PERK activation by palmitate also contributes to beta-cell apoptosis via CHOP. ..
  31. Alhusaini S, McGee K, Schisano B, Harte A, McTernan P, Kumar S, et al. Lipopolysaccharide, high glucose and saturated fatty acids induce endoplasmic reticulum stress in cultured primary human adipocytes: Salicylate alleviates this stress. Biochem Biophys Res Commun. 2010;397:472-8 pubmed publisher
    ..SFA showed significant activation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and activating transcription factor 6 (ATF6) and their down-stream targets...
  32. Egawa N, Yamamoto K, Inoue H, Hikawa R, Nishi K, Mori K, et al. The endoplasmic reticulum stress sensor, ATF6?, protects against neurotoxin-induced dopaminergic neuronal death. J Biol Chem. 2011;286:7947-57 pubmed publisher
  33. Isler J, Skalet A, Alwine J. Human cytomegalovirus infection activates and regulates the unfolded protein response. J Virol. 2005;79:6890-9 pubmed
    ..the UPR but specifically regulates the three branches of UPR signaling, PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE-1), to favor viral replication...
  34. Misra J, Chanda D, Kim D, Li T, Koo S, Back S, et al. Curcumin differentially regulates endoplasmic reticulum stress through transcriptional corepressor SMILE (small heterodimer partner-interacting leucine zipper protein)-mediated inhibition of CREBH (cAMP responsive element-binding protein H). J Biol Chem. 2011;286:41972-84 pubmed publisher
    ..cAMP responsive element-binding protein H (CREBH) and activating transcription factor 6 (ATF6) are both ER-bound bZIP family transcription factors that are activated upon ER stress...
  35. Yokouchi M, Hiramatsu N, Hayakawa K, Okamura M, Du S, Kasai A, et al. Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response. J Biol Chem. 2008;283:4252-60 pubmed
    ..O(2)(*) caused activation of the activating transcription factor 6-CCAAT/enhancer-binding protein-homologous protein (CHOP) and the inositol-requiring ER-to-nucleus ..
  36. Bommiasamy H, Back S, Fagone P, Lee K, Meshinchi S, Vink E, et al. ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum. J Cell Sci. 2009;122:1626-36 pubmed publisher
    ..These studies reveal further complexity in the potential relationships between UPR pathways, lipid production and ER biogenesis. ..
  37. Shen X, Ellis R, Sakaki K, Kaufman R. Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. PLoS Genet. 2005;1:e37 pubmed
    ..Finally, our array study identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution. ..
  38. Jheng J, Lau K, Tang W, Wu M, Horng J. Endoplasmic reticulum stress is induced and modulated by enterovirus 71. Cell Microbiol. 2010;12:796-813 pubmed publisher
    ..Epigenetic BiP overexpression alleviated EV71-induced ER stress and reduced viral protein expression and replication. Our results suggest that EV71 infection induces ER stress but modifies the outcome to assist viral replication. ..
  39. Thuerauf D, Morrison L, Glembotski C. Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction. J Biol Chem. 2004;279:21078-84 pubmed
    ..Thus, ATF6beta may serve as a transcriptional repressor functioning in part to regulate the strength and duration of ATF6alpha-mediated ERSRG activation during the ER stress response. ..
  40. Raciti G, Iadicicco C, Ulianich L, Vind B, Gaster M, Andreozzi F, et al. Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia. 2010;53:955-65 pubmed publisher
    ..protein 78 kDa (BIP/GRP78 [also known as HSPA5]), X-box binding protein-1 (XBP1) and activating transcription factor 6 (ATF6)...
  41. Chen X, Shen J, Prywes R. The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem. 2002;277:13045-52 pubmed
    ..These results show that ATF6 has a mechanism to sense ER stress and respond by translocation to the Golgi. ..
  42. Hiramatsu N, Joseph V, Lin J. Monitoring and manipulating mammalian unfolded protein response. Methods Enzymol. 2011;491:183-98 pubmed publisher
  43. Hapala I, Marza E, Ferreira T. Is fat so bad? Modulation of endoplasmic reticulum stress by lipid droplet formation. Biol Cell. 2011;103:271-85 pubmed publisher
    ..Taking into consideration recent data from the literature, we will try to draw possible mechanisms for the role of LDs in the regulation of ER homoeostasis and in ER-stress-related diseases. ..
  44. Galindo I, Hernaez B, Muñoz Moreno R, Cuesta Geijo M, Dalmau Mena I, Alonso C. The ATF6 branch of unfolded protein response and apoptosis are activated to promote African swine fever virus infection. Cell Death Dis. 2012;3:e341 pubmed publisher
    ..Thus, the capacity of ASFV to regulate the UPR may prevent early apoptosis and ensure viral replication...
  45. Fonseca S, Ishigaki S, Oslowski C, Lu S, Lipson K, Ghosh R, et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010;120:744-55 pubmed publisher
    ..These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes. ..
  46. Thuerauf D, Marcinko M, Belmont P, Glembotski C. Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability. J Biol Chem. 2007;282:22865-78 pubmed
    ..Thus, the relative levels of ATF6 alpha and -beta, may contribute to regulating the strength and duration of ATF6-dependent ERSR gene induction and cell viability. ..
  47. Chu W, Das S, Wang H, Chan J, Deloukas P, Froguel P, et al. Activating transcription factor 6 (ATF6) sequence polymorphisms in type 2 diabetes and pre-diabetic traits. Diabetes. 2007;56:856-62 pubmed
    b>Activating transcription factor 6 (ATF6) is located within the region of linkage to type 2 diabetes on chromosome 1q21-q23 and is a key activator of the endoplasmic reticulum stress response...
  48. Hoshino T, Nakaya T, Araki W, Suzuki K, Suzuki T, Mizushima T. Endoplasmic reticulum chaperones inhibit the production of amyloid-beta peptides. Biochem J. 2007;402:581-9 pubmed
    ..We consider that this up-regulation is a cellular protective response against Abeta. ..
  49. Hong M, Luo S, Baumeister P, Huang J, Gogia R, Li M, et al. Underglycosylation of ATF6 as a novel sensing mechanism for activation of the unfolded protein response. J Biol Chem. 2004;279:11354-63 pubmed
  50. Okada T, Yoshida H, Akazawa R, Negishi M, Mori K. Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response. Biochem J. 2002;366:585-94 pubmed
    ..Thus we propose that mammalian cells have evolved a strategy to cope with ER stress different from that of yeast cells. ..
  51. Thuerauf D, Morrison L, Hoover H, Glembotski C. Coordination of ATF6-mediated transcription and ATF6 degradation by a domain that is shared with the viral transcription factor, VP16. J Biol Chem. 2002;277:20734-9 pubmed
  52. Puri P, Mirshahi F, Cheung O, Natarajan R, Maher J, Kellum J, et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology. 2008;134:568-76 pubmed
    ..NASH is specifically associated with (1) failure to generate sXBP-1 protein and (2) activation of JNK. ..
  53. Tardif K, Mori K, Siddiqui A. Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J Virol. 2002;76:7453-9 pubmed
    ..These studies provide insight into the effects of HCV replication on intracellular events and the mechanisms underlying liver pathogenesis. ..