View Program - 63rd Annual Drosophila Research Conference

In eukaryotes, the endoplasmic reticulum (ER) serves as an essential organelle where membrane and secretory proteins undergo folding and maturation. Any physiological conditions that overwhelm the protein folding capacity of the ER could cause its dysfunction, widely referred to as “ER stress”. The ‘Unfolded protein response (UPR)” is a signaling mechanism that regulates gene expression in response to such ER stress. There are three classical UPR signaling pathways mediated by ER stress sensors IRE1, PERK, and ATF6 respectively, which are conserved in Drosophila. The best-characterized effector of the PERK pathway is a bZIP transcription factor ATF4. The 5’ UTR of ATF4 contains regulatory upstream open reading frames (uORFs) that block ATF4 expression in unstressed cells, but stimulates ATF4 translation specifically in response to PERK activation. We recently found that Xrp1 (bZIP transcription factor) is another effector of PERK that mediates an ATF4-independent branch of PERK signaling. Xrp1 mediates the induction of the anti-oxidant gene expression reporter, gstD-GFP, in response PERK activation. We found that Xrp1 also contains a regulatory 5’ UTR with uORFs. Mutation of the last uORF causes a de-repression of the main ORF expression even in an unstressed cells. We further examined the role of IRBP18, a Drosophila homolog of CEBPG that is known to form a heterodimer with Xrp1 during the regulation cell competition and repair of DNA breaks. We find that the IRBP18 is required for ER stress-induced gstD-GFP reporter expression. These results indicate that IRBP18 mediates an ATF4-independent branch of the unfolded protein response that may help maintain the redox equilibrium in cells under ER stress.

Deciphering an unrecognized role of bZIP transcription factor IRBP18 during unfolded protein response (UPR) in Drosophila