Signal Integration by the IκB Protein Pickle Shapes Drosophila Innate Host Defense.

Otto Morris,Haiyang Chen,Giuseppa Pennetta,Shaherin Basith,Celia Domingues,Andrea Chai,Nicolas Buchon,Xi Liu,Tencho Tenev,Sangdun Choi,Christopher Runchel,Pascal Meier

doi:10.1016/j.chom.2016.08.003

Abstract

SummaryPattern recognition receptors are activated following infection and trigger transcriptional programs important for host defense. Tight regulation of NF-κB activation is critical to avoid detrimental and misbalanced responses. We describe Pickle, a Drosophila nuclear IκB that integrates signaling inputs from both the Imd and Toll pathways by skewing the transcriptional output of the NF-κB dimer repertoire. Pickle interacts with the NF-κB protein Relish and the histone deacetylase dHDAC1, selectively repressing Relish homodimers while leaving other NF-κB dimer combinations unscathed. Pickle’s ability to selectively inhibit Relish homodimer activity contributes to proper host immunity and organismal health. Although loss of pickle results in hyper-induction of Relish target genes and improved host resistance to pathogenic bacteria in the short term, chronic inactivation of pickle causes loss of immune tolerance and shortened lifespan. Pickle therefore allows balanced immune responses that protect from pathogenic microbes while permitting the establishment of beneficial commensal host-microbe relationships.

Highlights

Host defense against pathogen invasion relies on potent inflammatory responses that are controlled by the NF-kB family of transcription factors (Hayden and Ghosh, 2008)
Pickle Negatively Regulates the NF-kB Transcription Factor Relish To identify regulators of NF-kB signaling, we performed an in vitro RNAi mini-screen of proteins that interact with the Drosophila NF-kB protein Relish (Guruharsha et al, 2011; Rhee et al, 2014)
Environment of S2* cells, we found that mere knockdown of loss of pickle resulted in hyper-activation of Relish pickle led to a dramatic induction (>5,000-fold) of the basal levels target genes following systemic infection, fat body-specific of Diptericin A (DiptA) and Diptericin B (DiptB) (Figure 4A)

Summary

Graphical Abstract

Tight regulation of NF-kB signaling is critical to avoid detrimental and misbalanced responses. Morris et al identify an IkB protein in Drosophila that inhibits a selective subset of the NF-kB dimer repertoire, thereby ensuring an appropriate immune response to pathogens while preventing tissue damage and reduced lifespan. 2016, Cell Host & Microbe 20, 283–295 September 14, 2016 a 2016 The Authors.

SUMMARY

INTRODUCTION

RESULTS

72 WB: α-FLAG

DISCUSSION

EXPERIMENTAL PROCEDURES