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Homologs of mammalian innate immune sensing and downstream pathway proteins have been discovered in a variety of basal invertebrates, including cnidarians and sponges, as well as some single-celled protists. Although the structures of these proteins vary among the basal organisms, many of the activities found in their mammalian counterparts are conserved. This is especially true for the Toll-like receptor (TLR) and cGAS-STING pathways that lead to downstream activation of transcription factor NF-κB. In this short perspective, we describe the evidence that TLR and cGAS-STING signaling to NF-κB is also involved in immunity in basal animals, as well as in the maintenance of microbial symbionts. Different from terrestrial animals, immunity in many marine invertebrates might have a constitutively active state (to protect against continual exposure to resident or waterborne microbes), as well as a hyperactive state that can be induced by pathogens at both transcriptional and posttranscriptional levels. Research on basal immunity may be important for (1) understanding different approaches that organisms take to sensing and protecting against microbes, as well as in maintaining microbial symbionts; (2) the identification of novel antimicrobial effector genes and processes; and (3) the molecular pathways that are being altered in basal marine invertebrates in the face of the effects of a changing environment. 

ABSTRACT The diversified NF-κB transcription factor family has been extensively characterized in organisms ranging from flies to humans. However, homologs of NF-κB and many upstream signaling components have recently been characterized in basal phyla, including Cnidaria (sea anemones, corals, hydras, and jellyfish), Porifera (sponges), and single-celled protists, including Capsaspora owczarzaki and some choanoflagellates. Herein, we review what is known about basal NF-κBs and how that knowledge informs on the evolution and conservation of key sequences and domains in NF-κB, as well as the regulation of NF-κB activity. The structures and DNA-binding activities of basal NF-κB proteins resemble those of mammalian NF-κB p100 proteins, and their posttranslational activation appears to have aspects of both canonical and noncanonical pathways in mammals. Several studies suggest that the single NF-κB proteins found in some basal organisms have dual roles in development and immunity. Further research on NF-κB in invertebrates will reveal information about the evolutionary roots of this major signaling pathway, will shed light on the origins of regulated innate immunity, and may have relevance to our understanding of the responses of ecologically important organisms to changing environmental conditions and emerging pathogen-based diseases. 

Abstract We provide a functional characterization of transcription factor NF-κB in protists and provide information about the evolution and diversification of this biologically important protein. We characterized NF-κB in two protists using phylogenetic, cellular, and biochemical techniques. NF-κB of the holozoan Capsaspora owczarzaki ( Co ) has an N-terminal DNA-binding domain and a C-terminal Ankyrin repeat (ANK) domain, and its DNA-binding specificity is more similar to metazoan NF-κB proteins than to Rel proteins. Removal of the ANK domain allows Co -NF-κB to enter the nucleus, bind DNA, and activate transcription. However, C-terminal processing of Co -NF-κB is not induced by IκB kinases in human cells. Overexpressed Co -NF-κB localizes to the cytoplasm in Co cells. Co -NF-κB mRNA and DNA-binding levels differ across three Capsaspora life stages. RNA-sequencing and GO analyses identify possible gene targets of Co -NF-κB. Three NF-κB-like proteins from the choanoflagellate Acanthoeca spectabilis ( As ) contain conserved Rel Homology domain sequences, but lack C-terminal ANK repeats. All three As -NF-κB proteins constitutively enter the nucleus of cells, but differ in their DNA-binding abilities, transcriptional activation activities, and dimerization properties. These results provide a basis for understanding the evolutionary origins of this key transcription factor and could have implications for the origins of regulated immunity in higher taxa.