TY - JOUR T1 - The integrated stress response pathway activates 4E-BP to bias mRNA translation and boost antimicrobial peptide synthesis in response to bacterial infection JF - bioRxiv DO - 10.1101/147629 SP - 147629 AU - Deepika Vasudevan AU - Nicholas K. Clark AU - Jessica Sam AU - Beatrix Ueberheide AU - Michael T. Marr AU - Hyung Don Ryoo Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/08/147629.abstract N2 - Pathogenic bacterial infection imposes considerable cellular stress on the host and often leads to attenuation of mRNA translation. In this translation-suppressive environment, it is unclear how the host synthesizes various antimicrobial peptides (AMPs) to mount innate immune response. Here, we use Drosophila as a model to demonstrate that AMP production during infection relies on a translation bias mechanism mediated by the inhibitor of cap-dependent translation 4E-BP (Drosophila Thor), and the AMP 5’UTRs that can undergo cap-independent translation. We found that 4E-BP is induced upon infection with the pathogenic bacteria Ecc15 by the stress-responsive transcription factor ATF4, and its upstream kinase GCN2. Moreover, loss of gcn2, atf4 or 4e-bp compromised immunity against Ecc15. In 4E-BP mutants, the transcriptional induction of AMPs after infection was unaffected, while the protein levels of AMPs were substantially reduced in their hemolymph. Analysis of the 5’UTRs of AMPs using cell-based bicistronic reporters and in vitro translation analysis indicated that AMPs are translated in a cap-independent mechanism. Analysis of bicistronic reporters in the presence of 4E-BP indicate that infection enhances cap-independent translational activity associated with AMP 5’UTRs, accounting for enhanced AMP translation during infection.Highlights 4E-BP is transcriptionally induced by GCN2/ATF signaling in response to bacterial infection4E-BP mutants show unaltered antimicrobial peptide (AMP) transcript levels, but have reduced AMP translationAMP 5’UTRs are translated cap-independentlyTranslation bias by 4E-BP drives cap-independent AMP translation ER -