Looking Down on NF-<i>κ</i>B

Williams, Leah M.; Gilmore, Thomas D.

doi:10.1128/mcb.00104-20

Cited by 95 publications

(88 citation statements)

References 69 publications

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“…Also noteworthy is the overexpression of programmed cell death 2‐like (PDCD2L) at 72 hr. PDCD2L down‐regulates the activity of NF‐kB, a master transcriptional regulator of immunity (reviewed by Williams & Gilmore, 2020).…”

Section: Resultsmentioning

confidence: 99%

Dual RNA‐sequencing analyses of a coral and its native symbiont during the establishment of symbiosis

et al. 2020

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Despite the ecological significance of the mutualistic relationship between Symbiodiniaceae and reef-building corals, the molecular interactions during establishment of this relationship are not well understood. This is particularly true of the transcriptional changes that occur in the symbiont. In the current study, a dual RNAsequencing approach was used to better understand transcriptional changes on both sides of the coral-symbiont interaction during the colonization of Acropora tenuis by a compatible Symbiodiniaceae strain (Cladocopium goreaui; ITS2 type C1). Comparison of transcript levels of the in hospite symbiont 3, 12, 48 and 72 hr after exposure to those of the same strain in culture revealed that extensive and generalized down-regulation of symbiont gene expression occurred during the infection process. Included in this "symbiosis-derived transcriptional repression" were a range of stress response and immune-related genes. In contrast, a suite of symbiont genes implicated in metabolism was upregulated in the symbiotic state. The coral data support the hypothesis that immune-suppression and arrest of phagosome maturation play important roles during the establishment of compatible symbioses, and additionally imply the involvement of some SCRiP family members in the colonization process. Consistent with previous ecological studies, the transcriptomic data suggest that active translocation of metabolites to the host may begin early in the colonization process, and thus that the mutualistic relationship can be established at the larval stage. This dual RNA-sequencing study provides insights into the transcriptomic remodelling that occurs in C. goreaui during transition to a symbiotic lifestyle and the novel coral genes implicated in symbiosis.

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Section: Resultsmentioning

confidence: 99%

Dual RNA‐sequencing analyses of a coral and its native symbiont during the establishment of symbiosis

et al. 2020

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“…NF-κB, typically composed of p50 and p65 subunits, can be activated by a wide range of signals such as TNF-α, LPS, IL-1, or LPA. After stimulation, IκB kinases are activated and degrade the inhibitory IκB protein, freeing up NF-κB 42 , 43 . Of note, NF-κB plays a critical role as a master regulator of inflammation, a process that has well-established links to cancer 44 , 45 .…”

Section: Discussionmentioning

confidence: 99%

MARCKS cooperates with NKAP to activate NF-kB signaling in smoke-related lung cancer

Li¹,

Chen²,

Hsu³

et al. 2021

Theranostics

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Rationale: Cigarette smoking is a major risk factor for lung cancer development and progression; however, the mechanism of how cigarette smoke activates signaling pathways in promoting cancer malignancy remains to be established. Herein, we aimed to determine the contribution of a signaling protein, myristoylated alanine-rich C kinase substrate (MARCKS), in smoke-mediated lung cancer. Methods: We firstly examined the levels of phosphorylated MARCKS (phospho-MARCKS) in smoke-exposed human lung cancer cells and specimens as well as non-human primate airway epithelium. Next, the MARCKS-interactome and its gene networks were identified. We also used genetic and pharmacological approaches to verify the functionality and molecular mechanism of smoke-induced phospho-MARCKS. Results: We observed that MARCKS becomes activated in airway epithelium and lung cancer cells in response to cigarette smoke. Functional proteomics revealed MARCKS protein directly binds to NF-κB-activating protein (NKAP). Following MARCKS phosphorylation at ser159 and ser163, the MARCKS-NKAP interaction was inhibited, leading to the activation of NF-κB signaling. In a screen of two cohorts of lung cancer patients, we confirmed that phospho-MARCKS is positively correlated with phospho-NF-κB (phospho-p65), and poor survival. Surprisingly, smoke-induced phospho-MARCKS upregulated the expression of pro-inflammatory cytokines, epithelial-mesenchymal transition, and stem-like properties. Conversely, targeting of MARCKS phosphorylation with MPS peptide, a specific MARCKS phosphorylation inhibitor, suppressed smoke-mediated NF-κB signaling activity, pro-inflammatory cytokines expression, aggressiveness and stemness of lung cancer cells. Conclusion: Our results suggest that phospho-MARCKS is a novel NF-kB activator in smoke-mediated lung cancer progression and provide a promising molecular model for developing new anticancer strategies.

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“…Transcription factor NF-κB (Nuclear Factor-κB) has been extensively studied for its roles in development and immunity in animals from sponges to humans (1)(2)(3). Only within the last few years has it been discovered that NF-κB's appearance pre-dates metazoan life; that is, that certain single-cell eukaryotes, namely some choanoflagellates and the holozoan Capsaspora owczarzaki, also contain genes encoding NF-κB-like proteins (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…One subgroup includes the traditional NF-κB proteins (p52/p100, p50/p105, Relish) that contain C-terminal inhibitory repeats known as Ankyrin repeats (ANK), whereas the second group consists of the Rel proteins (RelA, RelB, cRel, Dorsal, Dif) that contain C-terminal transactivation domains. Among basal organisms---including cnidarians, poriferans, and some protists---only NF-κB-like proteins have been found (3). Indeed, no Rel proteins have been identified in any organism basal to flies.…”

Section: Introductionmentioning

confidence: 99%

“…Transcriptomic and genomic sequencing has revealed that NF-κB and homologs of many of its upstream regulators are present in most eukaryotes from protists to vertebrates (3, 14). However, the numbers and structures of these signaling proteins vary across species, and generally become more complex and numerous through evolutionary time (14).…”

Section: Introductionmentioning

confidence: 99%

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Diversification of Transcription Factor NF-κB in Protists

Williams

Sridhar

Samaroo

et al. 2021

Preprint

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In this report, we investigate the evolution of transcription factor NF-κB by examining its structure, activity, and regulation in two protists using phylogenetic, cellular, and biochemical techniques. In Capsaspora owczarzaki (Co), we find that full-length NF-κB has an N-terminal DNA-binding domain and a C-terminal Ankyrin (ANK) repeat inhibitory domain, and its DNA-binding activity is more similar to metazoan NF-κB rather than Rel proteins. As with mammalian NF-κB proteins, removal of the ANK repeats is required for Co-NF-κB to enter the nucleus, bind DNA, and activate transcription. However, C-terminal processing of Co-NF-κB is not induced by co-expression of IKK in human cells. Exogenously expressed Co-NF-κB localizes to the nucleus in Co cells. NF-κB mRNA and DNA-binding levels differ across three life stages of Capsaspora, suggesting distinct roles for NF-κB in these life stages. RNA-seq and GO analyses identify possible gene targets and biological functions of Co-NF-κB. We also show that three NF-κB-like proteins from the choanoflagellate Acanthoeca spectabilis (As) all consist of primarily the N-terminal conserved Rel Homology domain sequences of NF-κB, and lack C-terminal ANK repeats. All three As-NF-κB proteins constitutively enter the nucleus of human and Co cells, but differ in their DNA-binding and transcriptional activation activities. Furthermore, all three As-NF-κB proteins can form heterodimers, indicating that NF-κB diversified into multi-subunit families at least two times during evolution. Overall, these results present the first functional characterization of NF-κB in a taxonomic kingdom other than Animalia and provide information about the evolution and diversification of this biologically important transcription factor.

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Looking Down on NF-κB

Cited by 95 publications

References 69 publications

Dual RNA‐sequencing analyses of a coral and its native symbiont during the establishment of symbiosis

Dual RNA‐sequencing analyses of a coral and its native symbiont during the establishment of symbiosis

MARCKS cooperates with NKAP to activate NF-kB signaling in smoke-related lung cancer

Diversification of Transcription Factor NF-κB in Protists

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