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.
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-N(9)-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.
Yoshida
H
H
Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8304, Japan.
Okada
T
T
Haze
K
K
Yanagi
H
H
Yura
T
T
Negishi
M
M
Mori
K
K
D051702:Activating Transcription Factor 6; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites / Q000235:genetics; D023081:CCAAT-Binding Factor / Q000737:chemistry / Q000378:metabolism*; D016384:Consensus Sequence; D004247:DNA / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D051790:G-Box Binding Factors; D006367:HeLa Cells; D006801:Humans; D046911:Macromolecular Substances; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D021122:Protein Subunits; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D050976:Basic-Leucine Zipper Transcription Factors; D023081:CCAAT-Binding Factor; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051790:G-Box Binding Factors; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D021122:Protein Subunits; D014157:Transcription Factors; D004247:DNA