ATF6 Is a Transcription Factor Specializing in the Regulation of Quality Control Proteins in the Endoplasmic Reticulum

Eukaryotic cells cope with endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR), a coordinated system of transcriptional and translational controls, which ensures the integrity of synthesized proteins. Mammalian cells express three UPR transducers in the ER, namely IRE1, PERK and ATF6. The IRE1 pathway, which is conserved from yeast to humans, mediates transcriptional induction of not only ER quality control proteins ( molecular chaperones, folding enzymes and components of ER-associated degradation) but also proteins working at various stages of secretion. The PERK pathway, conserved in metazoan cells, is responsible for translational control and also participates in transcriptional control in mammals. ATF6 is an ER-membrane-bound transcription factor activated by ER stress-induced proteolysis which consists of two closely related factors, ATF6 alpha and ATF6 beta, in mammals. ATF6 alpha but not ATF6 beta plays an important role in transcriptional control. In this study, we performed a genome-wide search for ATF6 alpha-target genes in mice. Only 30 of the 14,729 analyzable genes were identified as specific targets, of which 40% were ER quality control proteins, 20% were ER proteins, while the rest had miscellaneous functions. The negative effects of the absence of PERK on transcriptional induction of ER quality control proteins could be explained by its inhibitory effect on ATF6 alpha activation. Further, proteins involved in transport from the ER are not regulated by ATF6 alpha, and transport of folded cargo molecules from the ER was not affected by the absence of ATF6 alpha. Based on these results, we propose that ATF6 is a transcription factor specialized in the regulation of ER quality control proteins.