Opposing roles for ATF6α and ATF6β in endoplasmic reticulum stress response gene induction

The endoplasmic reticulum (ER) transmembrane proteins, ATF6α and ATF6β, are cleaved in response to ER stress, which can be induced by tunicamycin. The resulting N-terminal fragments of both ATF6 isoforms, which have conserved basic leucine-zipper and DNA binding domains but divergent transcriptional activation domains, translocate to the nucleus where they bind to ER stress-response elements (ERSE) in ER stress-response genes (ERSRG), such as GRP78. Although it is known that ATF6α is a potent activator of ERSRGs, the transcriptional potency and functions of ATF6β remain to be explored. Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β. Because ER stress activates nuclear translocation of both ATFGα and β and because both bind to ERSEs, the effect of co-expressing them on GRP78 induction was assessed. Surprisingly, N-ATF6β inhibited N-ATF6α-mediated GRP78 promoter activation in a dominant-negative manner. Moreover, N-ATF6β inhibited TN-mediated GRP78 promoter activation, which requires endogenous ATF6α. ATF6 isoform-specific small inhibitory RNAs were used to show that, as expected, endogenous ATF6α was required for maximal ERSRG induction; however, endogenous ATF6β moderated ERSRG induction. These results indicate that compared with ATF6α, ATF6β is a very poor activator of ERSRG induction and it represses ATF6α-mediated ERSRG induction. Thus, ATF6β may serve as a transcriptional represser functioning in part to regulate the strength and duration of ATF6α-mediated ERSRG activation during the ER stress response.