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Molecular and Cellular Biology, February 2001, p. 1239-1248, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1239-1248.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Hiderou Yoshida,1,2 Tetsuya Okada,1 Kyosuke Haze,2 Hideki Yanagi,2 Takashi Yura,2 Manabu Negishi,1 and Kazutoshi Mori1,*

Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8304,1 and HSP Research Institute, Kyoto Research Park, Shimogyo-ku, Kyoto 600-8813,2 Japan

Received 11 July 2000/Returned for modification 15 September 2000/Accepted 15 November 2000

The levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) are controlled by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element (ERSE), the consensus sequence of which is CCAAT-N9-CCACG. We recently proposed that ER stress response factor (ERSF) binding to ERSE is a heterologous protein complex consisting of the constitutive component NF-Y (CBF) binding to CCAAT and an inducible component binding to CCACG and identified the basic leucine zipper-type transcription factors ATF6alpha and ATF6beta as inducible components of ERSF. ATF6alpha and ATF6beta produced by ER stress-induced proteolysis bind to CCACG only when CCAAT is bound to NF-Y, a heterotrimer consisting of NF-YA, NF-YB, and NF-YC. Interestingly, the NF-Y and ATF6 binding sites must be separated by a spacer of 9 bp. We describe here the basis for this strict requirement by demonstrating that both ATF6alpha and ATF6beta physically interact with NF-Y trimer via direct binding to the NF-YC subunit. ATF6alpha and ATF6beta bind to the ERSE as a homo- or heterodimer. Furthermore, we showed that ERSF including NF-Y and ATF6alpha and/or beta  and capable of binding to ERSE is indeed formed when the cellular UPR is activated. 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.

* Corresponding author. Mailing address: Graduate School of Biostudies, Kyoto University, 46-29 Yoshida-Shimoadachi, Sakyo-ku, Kyoto 606-8304, Japan. Phone: 81-75-753-7687. Fax: 81-75-753-7688. E-mail: kazumori{at}ip.media.kyoto-u.ac.jp.

Molecular and Cellular Biology, February 2001, p. 1239-1248, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1239-1248.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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