Endoplasmic reticulum stress-induced formation of transcription factor complex ERSF including NF-Y (CBF) and activating transcription factors 6 alphaand 6 beta that activates the mammalian unfolded protein response
H. Yoshida et al., Endoplasmic reticulum stress-induced formation of transcription factor complex ERSF including NF-Y (CBF) and activating transcription factors 6 alphaand 6 beta that activates the mammalian unfolded protein response, MOL CELL B, 21(4), 2001, pp. 1239-1248
The levels of molecular chaperones and folding enzymes in the endoplasmic r
eticulum (ER) are controlled by a transcriptional induction process termed
the unfolded protein response (UPR). The mammalian UPR is mediated by the c
is-acting ER stress response element (ERSE), the consensus sequence of whic
h 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 c
onstitutive component NF-Y (CBF) binding to CCAAT and an inducible componen
t binding to CCACG and identified the basic leucine zipper-type transcripti
on factors ATF6 alpha and ATF6 beta as inducible components of ERSF. ATF6 a
lpha and ATF6 beta 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 separat
ed by a spacer of 9 bp. We describe here the basis for this strict requirem
ent by demonstrating that both ATF6 alpha and ATF6 beta physically interact
with NF-Y trimer via direct binding to the NF-YC subunit. ATF6 alpha and A
TF6 beta bind to the ERSE as a homo- or heterodimer. Furthermore, we showed
that ERSF including NF-Y and ATF6 alpha. and/or beta and capable of bindin
g 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 DN
A and adjacent protein NF-Y and that this complex formation process is esse
ntial for transcriptional induction of ER chaperones.