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

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.

Immune Regulation of Intestinal Stem Cell Proliferation and Differentiation in Drosophila

“…Here, IMD contributes to the delamination of damaged epithelial cells (44), and the expression of immuneregulatory molecules (45). Alterations to IMD have been linked to effects on the size and composition of the gut microbiome (15,(17)(18)(19)(20), and the lifespan of the fly (46)(47)(48)(49). In the adult, IMD also has complex roles in responses to enteric infections.…”

Extracts of Salvia-Nelumbinis Naturalis Ameliorate Nonalcoholic Steatohepatitis via Inhibiting Gut-Derived Endotoxin Mediated TLR4/NF-κB Activation

“…The phosphorylation of I κ B leads to its ubiquitylation and subsequent degradation, which allows the release of NF- κ B and its translocation to the nucleus. The most common heterodimer of NF- κ B is P65/P50 complex; subsequent to its translocation, P65 undergoes site-specific posttranslational modifications to further enhance the function [ 25 ]. We have analyzed the key molecules in the cascade pathway and found that SNN could inhibit the protein expression of TLR4, TIRAP, IRAK1/4, and TRAF6, which facilitate the phosphorylation of I κ B and activation of NF- κ B.…”

Pickle Flavors Relish in Drosophila Immunity

“…Pickle was shown to predominantly reside in the nuclear fraction, and the authors showed that Pickle regulates the Imd pathway at the level of RelN:RelN (RHD-containing N-terminal portion of the Relish) and suppresses the RelNdriven induction of AMPs. Interestingly, Pickle cannot inhibit Dif:RelN heterodimers and also cannot inhibit RelN:RelN homodimers when Dif:Dif homodimers are bound at the same promoter (Morris et al, 2016). However, the authors show that Pickle selectively co-purifies with the endogenous histone deacetylase dHDAC1 (also called Rpd3) from cellular extracts.…”

“…In this issue of Cell Host and Microbe, Morris et al (2016) describe a negative regulator of the Imd pathway, named Pickle. The authors identified Pickle as a member of the IkB superfamily by showing that Pickle contains seven ARRs in its C terminus, selectively binds to the RHD of Relish via its ARRs, and inhibits the activity of Relish.…”

“…In vivo knockdown of Pickle in the Drosophila fat body (an immune-responsive organ in flies that resembles the mammalian liver) leads to the hyper-activation of Imd signaling and the expression of Relish target genes in flies, which have been exposed to Gram-negative bacteria (Morris et al, 2016). As with many other negative regulators of immune pathways, the enhanced immune response via the removal of Pickle comes at the expense of life history traits, such as a decrease in the lifespan of the fly (Morris et al, 2016).…”