S-nitrosylation of the CLIP-protease, Persephone, Regulates Drosophila innate immunity

Abstract

Nitric oxide (NO) modulates innate immunity, but its molecular targets in Drosophila melanogaster are largely undefined. A key mechanism of NO signalling is S-nitrosylation, the modification of cysteine thiols. The homeostasis of S-nitrosylation is maintained by S-nitrosoglutathione reductase (Gsnor), encoded by the fdh gene in D. melanogaster. As reduced Gsnor activity enhances pathogen sensitivity in plants, we investigated its role in D. melanogaster. Here, we show that flies lacking fdh exhibit increased susceptibility to the fungus Beauveria bassiana and the bacterium Staphylococcus aureus, pathogens combatted by the Toll pathway. This immune deficiency correlates with impaired Toll-dependent antimicrobial peptide expression. We demonstrate that the Toll pathway protease Persephone (Psh) is S-nitrosylated in vivo and that loss of Gsnor prevents its proteolytic activation following infection. We propose a model where Gsnor-mediated regulation of NO is essential for Toll activation, preventing excessive S-nitrosylation of Psh and ensuring a robust immune response.