The GCN2-ATF4 Signaling Pathway Induces 4E-BP to Bias Translation and Boost Antimicrobial Peptide Synthesis in Response to Bacterial Infection

Abstract

Summary 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 (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’ untranslated regions (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.

The Toll Signaling Pathway Targets the Insulin-like Peptide Dilp6 to Inhibit Growth in Drosophila

“…Fat body Toll signaling exerts much more potent effects on circulating Dilp6 than on fat body Dilp6 transcripts, suggesting that Toll receptor activation regulates distinct targets that may control Dilp6 translation, secretion, or clearance from the circulation. Indeed, a decrease in Dilp6 translation would be consistent with an overall impairment in capdependent translation in cells with active immune signaling (Lemaitre and Girardin, 2013;Vasudevan et al, 2017).…”

Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR

“…eIF2D is a regulator of ATF4 mRNA translation. 4E-BP is an established transcriptional target of ATF4 in both Drosophila and mammals 10,[23][24][25][26] . Like mammals, Drosophila cells detect stress through conserved eIF2α kinases that activate ATF4-mediated ISR signaling [27][28][29] .…”

The integrated stress response regulates BMP signalling through effects on translation

“…For example, insulin signalling inhibits neurotransmitter release via d4E-BP-mediated repression of complexin mRNA translation [ 40 ], while dietary restriction enhances the expression of mitochondrial respiratory components by inducing d4E-BP [ 41 ]. Indeed, there is emerging evidence in Drosophila that ISR-induced d4E-BP plays a role in biasing translation during infection [ 42 ], development and aging [ 37 ].…”