Int. J. Dev. Biol. 61: 319 - 327 (2017)

https://doi.org/10.1387/ijdb.160250ao

Vol 61, Issue 3-4-5

Special Issue: Developmental Biology in Israel

The SUMO-targeted ubiquitin ligase, Dgrn, is essential for Drosophila innate immunity

Review | Published: 20 March 2017

Bella Koltun¹, Eliza Shackelford¹, François Bonnay², Nicolas Matt², Jean Marc Reichhart² and Amir Orian*^,1

¹Rappaport Research Institute and Rappaport Faculty of Medicine, Technion Integrated Cancer Center, Technion - Israel Institute of Technology, Haifa, Israel and ²UPR9022 du CNRS, Institut de Biologie Moléculaire et Cellulaire Université de Strasbourg, France

Abstract

The ability of metazoans to combat pathogenic infection involves both systemic and local responses to the invading pathogens. Ubiquitin and SUMO pathways molecularly regulate the response to infection, immune signaling and gene expression. Here, we report that Degringolade (Dgrn, CG10981), a SUMO-targeted ubiquitin ligase connecting the two pathways, is essential for the innate immunity response in Drosophila. dgrn^DK null and heterozygous mutant adult flies are severely immune-compromised and succumb rapidly to both pathogenic bacteria and fungi infections. The sensitivity to infection stems from the inability to produce multiple anti-microbial peptides, and transcriptional analyses suggest that the overexpression of Dgrn enhances the transcriptional output of the NF-ĸB related Toll and immune deficiency (IMD)-pathways. Moreover, expression of Dgrn alleviated the inhibitory impact of the cytoplasmic NF-ĸB inhibitor Cactus and the nuclear co-repressor Groucho/TLE (Gro). Additionally, we found that Dgrn is required for the local regenerative response of the mid-gut following infection. Upon oral infection, dgrn mutant flies fail to activate the Delta-Notch pathway in stem cells and enteroblasts, and are unable to regenerate and replace the damaged and dying enterocytes. Interestingly, the ubiquitin-specific protease CG8334 (dUSP32/dUSP11) antagonizes Dgrn activity in the gut, and halving the dose of CG8334 restores Delta-Notch signaling and rescues the lethality observed in dgrn mutants. Collectively, our data suggest that Dgrn is essential for both systemic and local tissue response to infection.

Keywords

Drosophila, innate-immunity, STUbL, SUMO, ubiquitin