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Gene Review

ATF6  -  activating transcription factor 6

Homo sapiens

Synonyms: ATF6-alpha, ATF6A, Activating transcription factor 6 alpha, Cyclic AMP-dependent transcription factor ATF-6 alpha, cAMP-dependent transcription factor ATF-6 alpha
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Disease relevance of ATF6


High impact information on ATF6

  • Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the gene upstream of XBP1 [6].
  • ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively [7].
  • Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress [7].
  • ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response [7].
  • Here, we report that glucose deprivation activated ATF6 but suppressed the SREBP2-regulated transcription [8].

Biological context of ATF6

  • Our results provide a novel mechanism by which ATF6 antagonizes SREBP2 to regulate the homeostasis of lipid and glucose [8].
  • Deletion analysis of the various functional domains of ATF6 indicated that the interaction was through its leucine-zipper domain [8].
  • ATF6 modulates SREBP2-mediated lipogenesis [8].
  • Of primary importance is a functional NF-Y complex and a high-affinity NF-Y binding site that confers selectivity among different ERSEs for ATF6 inducibility [9].
  • We propose that phosphorylation of ATF6 is a novel mechanism for augmenting its potential as a transcription activator [10].

Anatomical context of ATF6


Associations of ATF6 with chemical compounds

  • In addition, we have re-localized S1P and S2P to the ER with brefeldin A and find that the sequential cleavage of ATF6 is reconstituted in the ER [16].
  • This protein encoded by the G13 (cAMP response element binding protein-related protein) gene is constitutively synthesized as a type II transmembrane glycoprotein anchored in the ER membrane and processed into a soluble form upon ER stress as occurs with ATF6 [11].
  • We found that this luminal domain is required for the translocation of ATF6 to the Golgi and its subsequent cleavage, and we have mapped regions required for these properties [17].
  • Regulated intramembrane proteolysis of the factors SREBP and ATF6 represents a central control mechanism in sterol homeostasis and stress response within the endoplasmic reticulum [18].
  • Disulfide-bonded ATF6 is reduced upon treatment of cells with not only the reducing reagent dithiothreitol but also the glycosylation inhibitor tunicamycin, and the extent of reduction correlates with that of activation [19].
  • The associations were not replicated in 353 African-American case subjects and 182 control subjects, nor were ATF6 SNPs associated with altered insulin secretion or insulin sensitivity in nondiabetic Caucasian individuals [20].
  • Our results strengthen the evidence that one or more variants in ATF6 are associated with disturbed glucose homeostasis and DM2 [21].

Physical interactions of ATF6

  • In addition, we showed that YY1 interacts with ATF6 and in Tg-treated cells can enhance ATF6 activity [9].
  • A serine protease inhibitor prevents endoplasmic reticulum stress-induced cleavage but not transport of the membrane-bound transcription factor ATF6 [22].
  • These methods were used to investigate several key steps of ATF6 activation in the ER stress response including binding and dissociation of BiP to ATF6, translocation from the ER to the Golgi and cleavage in the Golgi [23].
  • Upon ER stress ATF6 is transported to the Golgi apparatus where it is cleaved to release its cytoplasmic domain [24].

Regulatory relationships of ATF6

  • XBP1 is also induced by activated ATF6 [25].
  • In contrast, mutant ATF6 representing the cytoplasmic region translocates into the nucleus and activates transcription of the endogenous GRP78/BiP gene [26].
  • DUSP12 was expressed significantly higher than ATF6 in a subset of the tumours [3].
  • In vitro DNA binding experiments showed that recombinant N-ATF6 beta inhibited the binding of recombinant N-ATF6 alpha to an ERSR element from the GRP78 promoter [27].

Other interactions of ATF6

  • Grp78 is a molecular chaperone involved in the unfolded protein response, the expression of which can be regulated by the transcription factors ATF6 and XBP1 [28].
  • The proteolytic processing of ATF6 and the G13 gene product is accompanied by their relocation from the ER to the nucleus; their basic regions seem to function as a nuclear localization signal [11].
  • We show that YY1 is an essential coactivator of ATF6 and uncover their specific interactive domains [29].
  • Higher accumulation of the grp78 product in the cytoplasm, concomitantly with marked nuclear localization of the activated ATF6 product (p50ATF6), was observed in moderately to poorly differentiated HCC tissues [28].
  • We demonstrate that HCV NS4B could induce activating transcription factor (ATF6) and inositol-requiring enzyme 1 (IRE1), to favor the HCV subreplicon and HCV viral replication [30].
  • Overexpression of NUCB1 inhibits S1P-mediated ATF6 cleavage without affecting ER-to-Golgi transport of ATF6, whereas knock-down of NUCB1 by siRNA accelerates ATF6 cleavage during ER stress [31].

Analytical, diagnostic and therapeutic context of ATF6

  • This new form of ATF6 was recovered as soluble nuclear protein by biochemical fractionation, correlating with enhanced nuclear localization of ATF6 as revealed by immunofluorescence [9].
  • Toward understanding the underlying mechanisms of these unique phenomena, we performed chromatin immunoprecipitation analyses, revealing that YY1 only occupies the Grp78 promoter upon ER stress and is mediated in part by the nuclear form of ATF6 [29].
  • METHODS: Expression of grp78, ATF6 and XBP1 was examined by Northern blot, RT-PCR, immunoblot and immunohistochemical analyses [28].
  • The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6 [32].
  • Although PERK and IRE1 are activated in the initial hours of reperfusion, total PERK decreases, ATF6 is not activated, and there is delayed appearance of UPR-induced mRNAs [33].


  1. Coordination of ATF6-mediated transcription and ATF6 degradation by a domain that is shared with the viral transcription factor, VP16. Thuerauf, D.J., Morrison, L.E., Hoover, H., Glembotski, C.C. J. Biol. Chem. (2002) [Pubmed]
  2. Induction of endoplasmic reticulum-induced stress genes in Panc-1 pancreatic cancer cells is dependent on Sp proteins. Abdelrahim, M., Liu, S., Safe, S. J. Biol. Chem. (2005) [Pubmed]
  3. Mapping and characterization of the amplicon near APOA2 in 1q23 in human sarcomas by FISH and array CGH. Kresse, S.H., Berner, J.M., Meza-Zepeda, L.A., Gregory, S.G., Kuo, W.L., Gray, J.W., Forus, A., Myklebost, O. Mol. Cancer (2005) [Pubmed]
  4. The unfolded protein response modulates toxicity of the expanded glutamine androgen receptor. Thomas, M., Yu, Z., Dadgar, N., Varambally, S., Yu, J., Chinnaiyan, A.M., Lieberman, A.P. J. Biol. Chem. (2005) [Pubmed]
  5. Biosynthesis and cellular trafficking of the convertase SKI-1/S1P: ectodomain shedding requires SKI-1 activity. Elagoz, A., Benjannet, S., Mammarbassi, A., Wickham, L., Seidah, N.G. J. Biol. Chem. (2002) [Pubmed]
  6. Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Kakiuchi, C., Iwamoto, K., Ishiwata, M., Bundo, M., Kasahara, T., Kusumi, I., Tsujita, T., Okazaki, Y., Nanko, S., Kunugi, H., Sasaki, T., Kato, T. Nat. Genet. (2003) [Pubmed]
  7. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Ye, J., Rawson, R.B., Komuro, R., Chen, X., Davé, U.P., Prywes, R., Brown, M.S., Goldstein, J.L. Mol. Cell (2000) [Pubmed]
  8. ATF6 modulates SREBP2-mediated lipogenesis. Zeng, L., Lu, M., Mori, K., Luo, S., Lee, A.S., Zhu, Y., Shyy, J.Y. EMBO J. (2004) [Pubmed]
  9. ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1. Li, M., Baumeister, P., Roy, B., Phan, T., Foti, D., Luo, S., Lee, A.S. Mol. Cell. Biol. (2000) [Pubmed]
  10. Requirement of the p38 mitogen-activated protein kinase signalling pathway for the induction of the 78 kDa glucose-regulated protein/immunoglobulin heavy-chain binding protein by azetidine stress: activating transcription factor 6 as a target for stress-induced phosphorylation. Luo, S., Lee, A.S. Biochem. J. (2002) [Pubmed]
  11. 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. Haze, K., Okada, T., Yoshida, H., Yanagi, H., Yura, T., Negishi, M., Mori, K. Biochem. J. (2001) [Pubmed]
  12. Endoplasmic reticulum stress as a correlate of cytotoxicity in human tumor cells exposed to diindolylmethane in vitro. Sun, S., Han, J., Ralph, W.M., Chandrasekaran, A., Liu, K., Auborn, K.J., Carter, T.H. Cell Stress Chaperones (2004) [Pubmed]
  13. Interaction of ATF6 and serum response factor. Zhu, C., Johansen, F.E., Prywes, R. Mol. Cell. Biol. (1997) [Pubmed]
  14. Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP. Gotoh, T., Oyadomari, S., Mori, K., Mori, M. J. Biol. Chem. (2002) [Pubmed]
  15. BiP binding keeps ATF6 at bay. Sommer, T., Jarosch, E. Dev. Cell (2002) [Pubmed]
  16. Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6. Shen, J., Prywes, R. J. Biol. Chem. (2004) [Pubmed]
  17. The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. Chen, X., Shen, J., Prywes, R. J. Biol. Chem. (2002) [Pubmed]
  18. CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P. Stirling, J., O'hare, P. Mol. Biol. Cell (2006) [Pubmed]
  19. Role of disulfide bridges formed in the luminal domain of ATF6 in sensing endoplasmic reticulum stress. Nadanaka, S., Okada, T., Yoshida, H., Mori, K. Mol. Cell. Biol. (2007) [Pubmed]
  20. Activating transcription factor 6 (ATF6) sequence polymorphisms in type 2 diabetes and pre-diabetic traits. Chu, W.S., Das, S.K., Wang, H., Chan, J.C., Deloukas, P., Froguel, P., Baier, L.J., Jia, W., McCarthy, M.I., Ng, M.C., Damcott, C., Shuldiner, A.R., Zeggini, E., Elbein, S.C. Diabetes (2007) [Pubmed]
  21. Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians. Meex, S.J., van Greevenbroek, M.M., Ayoubi, T.A., Vlietinck, R., van Vliet-Ostaptchouk, J.V., Hofker, M.H., Vermeulen, V.M., Schalkwijk, C.G., Feskens, E.J., Boer, J.M., Stehouwer, C.D., van der Kallen, C.J., de Bruin, T.W. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  22. A serine protease inhibitor prevents endoplasmic reticulum stress-induced cleavage but not transport of the membrane-bound transcription factor ATF6. Okada, T., Haze, K., Nadanaka, S., Yoshida, H., Seidah, N.G., Hirano, Y., Sato, R., Negishi, M., Mori, K. J. Biol. Chem. (2003) [Pubmed]
  23. ER stress signaling by regulated proteolysis of ATF6. Shen, J., Prywes, R. Methods (2005) [Pubmed]
  24. Reduction of disulfide bridges in the lumenal domain of ATF6 in response to glucose starvation. Nadanaka, S., Yoshida, H., Mori, K. Cell Struct. Funct. (2006) [Pubmed]
  25. Quantitative measurement of spliced XBP1 mRNA as an indicator of endoplasmic reticulum stress. Hirota, M., Kitagaki, M., Itagaki, H., Aiba, S. The Journal of toxicological sciences. (2006) [Pubmed]
  26. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Haze, K., Yoshida, H., Yanagi, H., Yura, T., Mori, K. Mol. Biol. Cell (1999) [Pubmed]
  27. Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability. Thuerauf, D.J., Marcinko, M., Belmont, P.J., Glembotski, C.C. J. Biol. Chem. (2007) [Pubmed]
  28. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. Shuda, M., Kondoh, N., Imazeki, N., Tanaka, K., Okada, T., Mori, K., Hada, A., Arai, M., Wakatsuki, T., Matsubara, O., Yamamoto, N., Yamamoto, M. J. Hepatol. (2003) [Pubmed]
  29. Endoplasmic reticulum stress induction of the Grp78/BiP promoter: activating mechanisms mediated by YY1 and its interactive chromatin modifiers. Baumeister, P., Luo, S., Skarnes, W.C., Sui, G., Seto, E., Shi, Y., Lee, A.S. Mol. Cell. Biol. (2005) [Pubmed]
  30. Hepatitis C virus non-structural protein NS4B can modulate an unfolded protein response. Zheng, Y., Gao, B., Ye, L., Kong, L., Jing, W., Yang, X., Wu, Z., Ye, L. J. Microbiol. (2005) [Pubmed]
  31. Nucleobindin 1 controls the unfolded protein response by inhibiting ATF6 activation. Tsukumo, Y., Tomida, A., Kitahara, O., Nakamura, Y., Asada, S., Mori, K., Tsuruo, T. J. Biol. Chem. (2007) [Pubmed]
  32. Induction of neuronal death by ER stress in Alzheimer's disease. Katayama, T., Imaizumi, K., Manabe, T., Hitomi, J., Kudo, T., Tohyama, M. J. Chem. Neuroanat. (2004) [Pubmed]
  33. Cerebral ischemia and the unfolded protein response. DeGracia, D.J., Montie, H.L. J. Neurochem. (2004) [Pubmed]
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