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1. An innate ability: How do basal invertebrates manage their chronic exposure to microbes?

   https://doi.org/10.1371/journal.ppat.1010897  

   Williams, Leah M.; Gilmore, Thomas D. (October 2022, PLOS Pathogens)

   Silverman, Neal (Ed.)

   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. 

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2. Comparison of NF-κB from the protists Capsaspora owczarzaki and Acanthoeca spectabilis reveals extensive evolutionary diversification of this transcription factor

   https://doi.org/10.1038/s42003-021-02924-2  

   Williams, Leah M.; Sridhar, Sainetra; Samaroo, Jason; Peart, Jada; Adindu, Ebubechi K.; Addanki, Anvitha; DiRusso, Christopher J.; BB522 Molecular Biology Laboratory; Alburi, Dana H. M.; Anisimov, Ludmila; et al (December 2021, Communications Biology)

   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 holozoanCapsaspora 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 allowsCo-NF-κB to enter the nucleus, bind DNA, and activate transcription. However, C-terminal processing ofCo-NF-κB is not induced by IκB kinases in human cells. OverexpressedCo-NF-κB localizes to the cytoplasm inCocells.Co-NF-κB mRNA and DNA-binding levels differ across threeCapsasporalife stages. RNA-sequencing and GO analyses identify possible gene targets ofCo-NF-κB. Three NF-κB-like proteins from the choanoflagellateAcanthoeca spectabilis(As) contain conserved Rel Homology domain sequences, but lack C-terminal ANK repeats. All threeAs-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. 

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3. Heterogeneous NF-κB activation and enhancer features shape transcription in Drosophila immunity

   https://doi.org/10.1101/2025.05.19.654881  

   Nawar, Noshin; Rits, Emma; Cohen, Lianne; Wunderlich, Zeba (May 2025, bioRxiv)

   Conserved NF-κB signaling pathways shape immune responses in animals. In mammals, NF-κB activation patterns and downstream transcription vary with stimulus, cell type, and stochastic differences among identically treated cells. Whether animals without adaptive immunity exhibit similar heterogeneity or rely on distinct immune strategies remains unknown. We engineered Drosophila melanogaster S2* reporter cells as an immune-responsive model to monitor the dynamics of an NF-κB transcription factor, Relish, and downstream transcription in single, living cells. Following immune stimulation, Relish exhibits diverse nuclear localization dynamics that fall into distinct categories, with both the fraction of responsive cells and their activation speed rising with stimulus dose. Pre-stimulus features, including Relish nuclear fraction, predict a cell's responsiveness to stimulation. Simultaneous measurement of Relish and downstream transcription revealed that the probability of transcriptional bursts from immune-responsive enhancers correlates with Relish nuclear fraction. The number of NF-κB binding sites tunes transcriptional activity among immune enhancers. Our study uncovers heterogeneity in NF-κB activation and target gene expression within Drosophila, illustrating how dynamic NF-κB behavior and enhancer architecture tune gene regulation. 

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4. Starvation decreases immunity and immune regulatory factor NF-κB in the starlet sea anemone Nematostella vectensis

   https://doi.org/10.1038/s42003-023-05084-7  

   Carrión, Pablo J.; Desai, Niharika; Brennan, Joseph J.; Fifer, James E.; Siggers, Trevor; Davies, Sarah W.; Gilmore, Thomas D. (December 2023, Communications Biology)

   Lack of proper nutrition has important consequences for the physiology of all organisms, and nutritional status can affect immunity, based on many studies in terrestrial animals. Here we show a positive correlation between nutrition and immunity in the sea anemoneNematostella vectensis. Gene expression profiling of adult anemones shows downregulation of genes involved in nutrient metabolism, cellular respiration, and immunity in starved animals. Starved adult anemones also have reduced protein levels and activity of immunity transcription factor NF-κB. Starved juvenile anemones have increased sensitivity to bacterial infection and also have lower NF-κB protein levels, as compared to fed controls. Weighted Gene Correlation Network Analysis (WGCNA) is used to identify significantly correlated gene networks that were downregulated with starvation. These experiments demonstrate a correlation between nutrition and immunity in an early diverged marine metazoan, and the results have implications for the survival of marine organisms as they encounter changing environments. 

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5. Brain rhythms control microglial response and cytokine expression via NF-κB signaling

   https://doi.org/10.1126/sciadv.adf5672  

   Prichard, Ashley; Garza, Kristie M; Shridhar, Avni; He, Christopher; Bitarafan, Sara; Pybus, Alyssa; Wang, Yunmiao; Snyder, Emma; Goodson, Matthew C; Franklin, Tina C; et al (August 2023, Science Advances)

   Microglia transform in response to changes in sensory or neural activity, such as sensory deprivation. However, little is known about how specific frequencies of neural activity, or brain rhythms, affect microglia and cytokine signaling. Using visual noninvasive flickering sensory stimulation (flicker) to induce electrical neural activity at 40 hertz, within the gamma band, and 20 hertz, within the beta band, we found that these brain rhythms differentially affect microglial morphology and cytokine expression in healthy animals. Flicker induced expression of certain cytokines independently of microglia, including interleukin-10 and macrophage colony-stimulating factor. We hypothesized that nuclear factor κB (NF-κB) plays a causal role in frequency-specific cytokine and microglial responses because this pathway is activated by synaptic activity and regulates cytokines. After flicker, phospho–NF-κB colabeled with neurons more than microglia. Inhibition of NF-κB signaling down-regulated flicker-induced cytokine expression and attenuated flicker-induced changes in microglial morphology. These results reveal a mechanism through which brain rhythms affect brain function by altering microglial morphology and cytokines via NF-κB. 

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