Abstract
Bacterial infection often leads to suppression of mRNA translation, but hosts are nonetheless able to express immune response genes through as yet unknown mechanisms. Here, we use a Drosophila model to demonstrate that antimicrobial peptide (AMP) production during infection is paradoxically stimulated by the inhibitor of cap-dependent translation, 4E-BP (eIF4E-binding protein; encoded by the Thor gene). We found that 4E-BP is induced upon infection with pathogenic bacteria by the stress-response transcription factor ATF4 and its upstream kinase, GCN2. Loss of gcn2, atf4, or 4e-bp compromised immunity. While AMP transcription is unaffected in 4e-bp mutants, AMP protein levels are substantially reduced. The 5′ UTRs of AMPs score positive in cap-independent translation assays, and this cap-independent activity is enhanced by 4E-BP. These results are corroborated in vivo using transgenic 5′ UTR reporters. These observations indicate that ATF4-induced 4e-bp contributes to innate immunity by biasing mRNA translation toward cap-independent mechanisms, thus enhancing AMP synthesis.
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•4E-BP induced by GCN2-ATF4 signaling in response to bacterial infection•4E-BP mutants show unaltered AMP transcript levels but have reduced AMP translation•AMP 5′ UTRs support cap-independent translation•Translation bias by 4E-BP drives cap-independent AMP translation
The cap-dependent translation inhibitor 4E-BP is induced during bacterial infection in Drosophila, and animals lacking 4E-BP are immunocompromised. How an effective innate immune response is mounted in a translation-suppressive environment and why 4E-BP is required in this process were unknown. Vasudevan et al. demonstrate that antimicrobial peptides, which are key components of the Drosophila innate immune response, are translated cap-independently via IRES-like elements in their 5′ UTRs and that their translation is enhanced by 4E-BP-mediated suppression of cap-dependent translation.