Evolution of TLR Signaling: A Sea Anemone Model has a Single Toll‐like Receptor with Roles in Pathogen Detection, NF‐κB Signal Transduction, and Development

Abstract

The innate immune system is the most primitive branch of the immune system and is responsible for recognizing pathogens and eliciting responses such as inflammation and antimicrobial peptide production in many organisms. Toll‐like receptors (TLRs) are transmembrane receptors that have been characterized in organisms from insects to humans. TLRs detect molecules expressed by microbial pathogens, and then activate the NF‐κB transcription factor signaling pathway to turn on the expression of innate immune effector genes. Recent genome and transcriptome sequencing efforts have led to the identification of TLR‐like genes in organisms more basal to insects, but the biological roles of these basal TLRs are not well understood. In this project, we are characterizing a TLR‐like protein in the sea anemone Nematostella vectensis (Nv), a model organism for the phylum Cnidaria. The single Nv‐TLR harbors leucine‐rich extracellular, transmembrane, and intracellular TIR domains, consistent with TLR structures in higher organisms, including humans. In cell culture‐based reporter assays, we show that Nv‐TLR can activate the human NF‐κB signaling pathway and this pathway activation can be stimulated by the biologically relevant bacterium Vibrio coralliilyticus and purified flagellin from Salmonella typhimurium. In biochemical studies, the intracellular TIR domain of Nv‐TLR can bind to human NF‐κB signal transduction adapter proteins MAL and MyD88, and the extracellular domain of Nv‐TLR can directly bind to flagellin. In anemones, Nv‐TLR and Nv‐NF‐κB (and most intermediate TLR to NF‐κB signaling proteins) are expressed in cnidocytes, both in the body column and in a Nematostella‐specific circulating organ called the nematosome. Nv‐TLR is also required for embryonic development in N. vectensis. Ongoing studies are characterizing the biochemical aspects of the flagellin‐TLR interaction. Taken together, these studies suggest that a TLR‐to‐NF‐κB pathway is functionally conserved from cnidarians to humans. Moreover, these studies provide insight into the evolutionary basis of vertebrate innate immunity, and shed light on how simple organisms respond at the molecular level to environmental and biological stressors.Support or Funding InformationUndergraduate Research Opportunities Program (Boston University), National Science Foundation, Arnold and Mabel Beckman FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.