Identification of ERSE-II, a new cis-actin element responsible for the ATF6-dependent mammalian unfolded protein response

Herp is a 54-kDa membrane protein in the endoplasmic reticulum (ER). The mR NA expression level of Herp is increased by the accumulation of unfolded pr oteins in the ER. Transcriptional changes designed to deal with this type o f ER stress is called the unfolded protein response (UPR). Most mammalian U PR-target genes encode ER resident molecular chaperones: GRP78, GRP94, and calreticulin. The promoter regions of these genes contain a cis-acting ER s tress response element, ERSE, with the consensus sequence of CCAAT-N-9-CCAC G. Under conditions of ER stress, p50ATF6 (the active form of the transcrip tion factor, ATF6) binds to CCACG when CCAAT is bound by the general transc ription factor, NF-Y/CBF. Here, we report the genomic structure of human He rp and the presence of a new ER stress response element, ERSE-II, in its pr omoter region. The gene for Herp consists of eight exons, localized to chro mosome 16q12.2-13. The promoter region contains a single ERSE-like sequence . In reporter gene assays, disruption of this cis-element resulted in a par tial reduction of the transcriptional response to ER stress, suggesting tha t the element is functional for the UPR. These results also suggest the inv olvement of additional elements in the UPR. Further analysis, using an opti mized plasmid containing an mRNA-destabilizing sequence, revealed ERSE-II ( ATTGG-N-CCACG) as the second ER stress response element. Interestingly, ERS E-II was also dependent on p50ATF6, in a manner similar to that of ERSE, de spite the disparate structure. The strong induction of Herp mRNA by ER stre ss would be achieved by the cooperation of ERSE and ERSE-II.