Charon Mediates Immune Deficiency–Driven PARP-1–Dependent Immune Responses in Drosophila

Abstract

Regulation of NF-kB nuclear translocation and stability is central to mounting an effective innate immune response. Here, we describe a novel molecular mechanism controlling NF-kB-dependent innate immune response. We show that a previously unknown protein, termed as Charon, functions as a regulator of antibacterial and antifungal immune defense in Drosophila. Charon is an ankyrin repeat-containing protein that mediates PARP-1-dependent transcriptional responses downstream of the innate immune pathway. Our results demonstrate that Charon interacts with the NF-kB orthologue Relish inside perinuclear particles and delivers active Relish to PARP-1-bearing promoters, thus triggering NF-kB/PARP-1-dependent transcription of antimicrobial peptides. Ablating the expression of Charon prevents Relish from targeting promoters of antimicrobial genes and effectively suppresses the innate immune transcriptional response. Together, these results implicate Charon as an essential mediator of PARP-1-dependent transcription in the innate immune pathway. Thus, our results are the first to describe the molecular mechanism regulating translocation of the NF-kB subunit from cytoplasm to chromatin.

The Kinase IKKβ Regulates a STING- and NF-κB-Dependent Antiviral Response Pathway in Drosophila

“…NF-ĸB transcription factors bind DNA as homo- or hetero-dimers, which regulate distinct yet overlapping programs (Zhang et al, 2017). Of note, one of the ten genes that we identified as regulated by DCV and dIKKβ in cells and in flies is Charon , also known as pickle (Ji et al, 2016; Morris et al, 2016). This gene encodes an IĸB protein, which acts as a selective inhibitor of Relish homodimers, without affecting the heterodimers formed by Relish with the two other NF-ĸB proteins in flies, namely Dorsal and DIF (Morris et al, 2016).…”

Dietary Adaptation of Microbiota in Drosophila Requires NF-κB-Dependent Control of the Translational Regulator 4E-BP

“…The transcriptional activation function of Relish is required for the expression of a large network of innate-immune-inducible genes. However, we have previously shown that Relish can also limit the inducibility of specific genes through promoter and enhancer (P/E) binding in Drosophila (Ji et al, 2016;Molaei et al, 2019). Using the open-access JASPAR CORE insecta database (Khan et al, 2018), we identified multiple, conserved NF-kB DNA binding motifs (kB sequence sites identified as GGG R N YYYYY) in the upstream P/E of the Thor locus (Fig- ure 4A).…”

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…Oxidative stress, bacterial products (LPS) and inflammatory cytokines (IL-1, TNFα), all of which activate PARP-1, also activate NF-κB. PARP-1 sustains Toll-Like Receptors (TLRs)-induced NF-κB activation [34], a pathway involved not only in inflammation but also in carcinogenesis [35]. NF-κB activation and nuclear translocation require phosphorylation of I-κB inhibitors by the IκB kinase (IKK), an enzymatic complex including the regulatory element IKKγ, also known as NF-κB essential modulator (NEMO).…”