Opposing Roles for ATF6α and ATF6β in Endoplasmic Reticulum Stress Response Gene Induction*

By D. Thuerauf, L. Morrison, C. Glembotski. Journal of Biological Chemistry, 2004

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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 ATF6α 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 repressor functioning in part to regulate the strength and duration of ATF6α-mediated ERSRG activation during the ER stress response.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2904daea26162025c1e98769a9ffaece845c94e2