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. 2001 Apr 1;355(Pt 1):19–28. doi: 10.1042/0264-6021:3550019

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.

K Haze 1, T Okada 1, H Yoshida 1, H Yanagi 1, T Yura 1, M Negishi 1, K Mori 1
PMCID: PMC1221707  PMID: 11256944

Abstract

Eukaryotic cells control the levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element consisting of 19 nt (CCAATN(9)CCACG), the CCACG part of which is considered to provide specificity. We recently identified the basic leucine zipper (bZIP) protein ATF6 as a mammalian UPR-specific transcription factor; ATF6 is activated by ER stress-induced proteolysis and binds directly to CCACG. Here we report that eukaryotic cells express another bZIP protein closely related to ATF6 in both structure and function. 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. 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. Overexpression of the soluble form of the G13 product constitutively activates the UPR, whereas overexpression of a mutant lacking the activation domain exhibits a strong dominant-negative effect. Furthermore, the soluble forms of ATF6 and the G13 gene product are unable to bind to several point mutants of the cis-acting ER stress response element in vitro that hardly respond to ER stress in vivo. 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.

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Selected References

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  1. Bertolotti A., Zhang Y., Hendershot L. M., Harding H. P., Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000 Jun;2(6):326–332. doi: 10.1038/35014014. [DOI] [PubMed] [Google Scholar]
  2. Cox J. S., Shamu C. E., Walter P. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell. 1993 Jun 18;73(6):1197–1206. doi: 10.1016/0092-8674(93)90648-a. [DOI] [PubMed] [Google Scholar]
  3. Dingwall C., Laskey R. A. Nuclear targeting sequences--a consensus? Trends Biochem Sci. 1991 Dec;16(12):478–481. doi: 10.1016/0968-0004(91)90184-w. [DOI] [PubMed] [Google Scholar]
  4. Gething M. J., Sambrook J. Protein folding in the cell. Nature. 1992 Jan 2;355(6355):33–45. doi: 10.1038/355033a0. [DOI] [PubMed] [Google Scholar]
  5. 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 Nov;10(11):3787–3799. doi: 10.1091/mbc.10.11.3787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Helenius A., Marquardt T., Braakman I. The endoplasmic reticulum as a protein-folding compartment. Trends Cell Biol. 1992 Aug;2(8):227–231. doi: 10.1016/0962-8924(92)90309-b. [DOI] [PubMed] [Google Scholar]
  7. Kaufman R. J. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 1999 May 15;13(10):1211–1233. doi: 10.1101/gad.13.10.1211. [DOI] [PubMed] [Google Scholar]
  8. Khanna A., Campbell R. D. The gene G13 in the class III region of the human MHC encodes a potential DNA-binding protein. Biochem J. 1996 Oct 1;319(Pt 1):81–89. doi: 10.1042/bj3190081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kozutsumi Y., Segal M., Normington K., Gething M. J., Sambrook J. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature. 1988 Mar 31;332(6163):462–464. doi: 10.1038/332462a0. [DOI] [PubMed] [Google Scholar]
  10. Kyte J., Doolittle R. F. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982 May 5;157(1):105–132. doi: 10.1016/0022-2836(82)90515-0. [DOI] [PubMed] [Google Scholar]
  11. Li M., Baumeister P., Roy B., Phan T., Foti D., Luo S., Lee A. S. ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1. Mol Cell Biol. 2000 Jul;20(14):5096–5106. doi: 10.1128/mcb.20.14.5096-5106.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Li W. W., Alexandre S., Cao X., Lee A. S. Transactivation of the grp78 promoter by Ca2+ depletion. A comparative analysis with A23187 and the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin. J Biol Chem. 1993 Jun 5;268(16):12003–12009. [PubMed] [Google Scholar]
  13. Li W. W., Sistonen L., Morimoto R. I., Lee A. S. Stress induction of the mammalian GRP78/BiP protein gene: in vivo genomic footprinting and identification of p70CORE from human nuclear extract as a DNA-binding component specific to the stress regulatory element. Mol Cell Biol. 1994 Aug;14(8):5533–5546. doi: 10.1128/mcb.14.8.5533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Min J., Shukla H., Kozono H., Bronson S. K., Weissman S. M., Chaplin D. D. A novel Creb family gene telomeric of HLA-DRA in the HLA complex. Genomics. 1995 Nov 20;30(2):149–156. doi: 10.1006/geno.1995.9891. [DOI] [PubMed] [Google Scholar]
  15. Mori K., Ma W., Gething M. J., Sambrook J. A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus. Cell. 1993 Aug 27;74(4):743–756. doi: 10.1016/0092-8674(93)90521-q. [DOI] [PubMed] [Google Scholar]
  16. Mori K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell. 2000 May 26;101(5):451–454. doi: 10.1016/s0092-8674(00)80855-7. [DOI] [PubMed] [Google Scholar]
  17. Niwa M., Sidrauski C., Kaufman R. J., Walter P. A role for presenilin-1 in nuclear accumulation of Ire1 fragments and induction of the mammalian unfolded protein response. Cell. 1999 Dec 23;99(7):691–702. doi: 10.1016/s0092-8674(00)81667-0. [DOI] [PubMed] [Google Scholar]
  18. Roy B., Lee A. S. The mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress-inducible complex. Nucleic Acids Res. 1999 Mar 15;27(6):1437–1443. doi: 10.1093/nar/27.6.1437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Roy B., Li W. W., Lee A. S. Calcium-sensitive transcriptional activation of the proximal CCAAT regulatory element of the grp78/BiP promoter by the human nuclear factor CBF/NF-Y. J Biol Chem. 1996 Nov 15;271(46):28995–29002. doi: 10.1074/jbc.271.46.28995. [DOI] [PubMed] [Google Scholar]
  20. Tanaka M., Herr W. Differential transcriptional activation by Oct-1 and Oct-2: interdependent activation domains induce Oct-2 phosphorylation. Cell. 1990 Feb 9;60(3):375–386. doi: 10.1016/0092-8674(90)90589-7. [DOI] [PubMed] [Google Scholar]
  21. Tirasophon W., Welihinda A. A., Kaufman R. J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 1998 Jun 15;12(12):1812–1824. doi: 10.1101/gad.12.12.1812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Urano F., Wang X., Bertolotti A., Zhang Y., Chung P., Harding H. P., Ron D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000 Jan 28;287(5453):664–666. doi: 10.1126/science.287.5453.664. [DOI] [PubMed] [Google Scholar]
  23. Virbasius C. M., Wagner S., Green M. R. A human nuclear-localized chaperone that regulates dimerization, DNA binding, and transcriptional activity of bZIP proteins. Mol Cell. 1999 Aug;4(2):219–228. doi: 10.1016/s1097-2765(00)80369-x. [DOI] [PubMed] [Google Scholar]
  24. Wang X. Z., Harding H. P., Zhang Y., Jolicoeur E. M., Kuroda M., Ron D. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 1998 Oct 1;17(19):5708–5717. doi: 10.1093/emboj/17.19.5708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Yoshida H., Haze K., Yanagi H., Yura T., Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem. 1998 Dec 11;273(50):33741–33749. doi: 10.1074/jbc.273.50.33741. [DOI] [PubMed] [Google Scholar]
  26. Yoshida H., Okada T., Haze K., Yanagi H., Yura T., Negishi M., Mori K. 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 Sep;20(18):6755–6767. doi: 10.1128/mcb.20.18.6755-6767.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Zhu C., Johansen F. E., Prywes R. Interaction of ATF6 and serum response factor. Mol Cell Biol. 1997 Sep;17(9):4957–4966. doi: 10.1128/mcb.17.9.4957. [DOI] [PMC free article] [PubMed] [Google Scholar]

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