Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway

Roy, Payel; Mukherjee, Tapas; Chatterjee, B. B.; Vijayaragavan, Bharath; Banoth, Balaji; Basak, Soumen

doi:10.1038/onc.2016.309

Cited by 38 publications

(52 citation statements)

References 51 publications

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“…Despite the attenuated NIK:IKK1 activity, a lack of p100‐IκBδ alleviated TNF‐mediated suppressions of the RelB activity and chemokine gene expressions. In fact, we detected an increase in the RelB activity in response to TNF in Nfkb2 −/− MEFs that was noted earlier and attributed to the autoregulatory RelB synthesis (Roy et al , ). We also expressed the mature p52 subunit from a transgene in Nfkb2 −/− MEFs that led to a constitutive RelB activity mostly composed of the RelB:p52 dimer (Fig EV4I–K).…”

Section: Resultssupporting

confidence: 81%

A TNF ‐p100 pathway subverts noncanonical NF ‐κB signaling in inflamed secondary lymphoid organs

et al. 2017

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Lymphotoxin-beta receptor (LTβR) present on stromal cells engages the noncanonical NF-κB pathway to mediate RelB-dependent expressions of homeostatic chemokines, which direct steady-state ingress of naïve lymphocytes to secondary lymphoid organs (SLOs). In this pathway, NIK promotes partial proteolysis of p100 into p52 that induces nuclear translocation of the RelB NF-κB heterodimers. Microbial infections often deplete homeostatic chemokines; it is thought that infection-inflicted destruction of stromal cells results in the downregulation of these chemokines. Whether inflammation also regulates these processes remains unclear. We show that TNF accumulated upon non-infectious immunization of mice similarly downregulates the expressions of these chemokines and consequently diminishes the ingress of naïve lymphocytes in inflamed SLOs. Mechanistically, TNF inactivated NIK in LTβR-stimulated cells and induced the synthesis of mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity as inhibitory IκBδ. Finally, a lack of p100 alleviated these TNF-mediated inhibitions in inflamed SLOs of immunized mice. In sum, we reveal that an inhibitory TNF-p100 pathway modulates the adaptive compartment during immune responses.

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Section: Resultssupporting

confidence: 81%

A TNF ‐p100 pathway subverts noncanonical NF ‐κB signaling in inflamed secondary lymphoid organs

et al. 2017

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“…380/15). As described earlier (45), MEFs generated from embryonic day 13.5 (E13.5) embryos were used either as primary cells or subsequent to their immortalization by the NIH 3T3 protocol. Unless otherwise mentioned, experiments were performed using primary MEFs.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…Biochemical analyses. MEFs were harvested at different times postinfection; whole-cell extracts and nuclear extracts were analyzed by immunoblotting and EMSA, respectively (45). NF-B-related antibodies have been described earlier (45).…”

Section: Cells and Virusesmentioning

confidence: 99%

“…MEFs were harvested at different times postinfection; whole-cell extracts and nuclear extracts were analyzed by immunoblotting and EMSA, respectively (45). NF-B-related antibodies have been described earlier (45). CHPV-related anti-N, anti-M, and anti-P antibodies were obtained as a gift from National Institute of Virology (NIV), Pune, India.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…RNA analyses. Total RNA was isolated from infected MEFs, and RT-qPCR analyses were conducted, as described previously (45). The following primers were used in this study: for the CHPV genome, CGAGTGAACTCAGTTGCAGAG (forward) and GAATCGAGAGTGTCCTGAAGC (reverse); CHPV-N, GATTTGT TGCGGATGATGAC (forward) and CCAGAAATGGAAACTGGGAT (reverse); CHPV-P, CTCTCCGTCTGATCCA CCTT (forward) and TCAATCCAGCAATGACCAGT (reverse); mIFN␤, CCGGACTTCAAGATCCCTATGGA (forward) and TGGCAAAGGCAGTGTAACTCTTC (reverse); ISG-15, AGCTCCATGTCGGTGTCAG (forward) and GAAGGTCAGCCAGAACAGGT (reverse); OAS-1, AGGGGCATTTGCTGCTCTGC (forward) and GGGCACCTGC TGTGGTTTATTG (reverse); CXCL10, AGACATCCCGAGCCAACCTT (forward) and GTTAAGGAGCCCTT TT AGAC (reverse); CXCL16, TGGAACTGGTCATGGGAAGAG (forward) and GGGTACTGGCTTGAGGCAAA (reverse); cIAP2, GAAGTGGGCTGCGGTATCA (forward) and GCGCTGTCTTGAACCATGTTC (reverse); MnSOD, TCAATGGTGGGGGACATATT (forward) and GCTTGATAGCCTCCAGCAAC (reverse); TRAF1, GGAGGCATCCT TTGATGGTA (forward) and AGGGACAGGTGGGTCTTCTT (reverse); cFOS, CCTTCGGATTCTCCGTTTCTCT (forward) and TGGTGAAGACCGTGTCAGGA (reverse); ISG56, GTCCGGTTAAATCCAGAAGATCC (forward) and TAGCTTTGGCAAGATGTGCTG (reverse); actin, CCAACCGTGAAAAGATGAC (forward) and GTACGACC AGAGGCATACAG (reverse).…”

Section: Cells and Virusesmentioning

confidence: 99%

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Chandipura Virus Utilizes the Prosurvival Function of RelA NF-κB for Its Propagation

Bais

Ratra

Khan

et al. 2019

J Virol

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Chandipura virus (CHPV), a cytoplasmic RNA virus, has been implicated in several outbreaks of acute encephalitis in India. Despite the relevance of CHPV to human health, how the virus interacts with the host signaling machinery remains obscure. In response to viral infections, mammalian cells activate RelA/NF-B heterodimers, which induce genes encoding interferon beta (IFN-␤) and other immune mediators. Therefore, RelA is generally considered to be an antiviral transcription factor. However, RelA activates a wide spectrum of genes in physiological settings, and there is a paucity of direct genetic evidence substantiating antiviral RelA functions. Using mouse embryonic fibroblasts, we genetically dissected the role of RelA in CHPV pathogenesis. We found that CHPV indeed activated RelA and that RelA deficiency abrogated the expression of IFN-␤ in response to virus infections. Unexpectedly, infection of Rela Ϫ/Ϫ fibroblasts led to a decreased CHPV yield. Our investigation clarified that RelA-dependent synthesis of prosurvival factors restrained infection-inflicted cell death and that exacerbated cell death processes prevented multiplication of CHPV in RelAdeficient cells. Chikungunya virus, a cytopathic RNA virus associated also with epidemics, required RelA, and Japanese encephalitis virus, which produced relatively minor cytopathic effects in fibroblasts, circumvented the need of RelA for their propagation. In sum, we documented a proviral function of the pleiotropic factor RelA linked to its prosurvival properties. RelA promoted the growth of cytopathic RNA viruses by extending the life span of infected cells, which serve as the replicative niche of intracellular pathogens. We argue that our finding bears significance for understanding host-virus interactions and may have implications for antiviral therapeutic regimes. IMPORTANCE RelA/NF-B participates in a wide spectrum of physiological processes, including shaping immune responses against invading pathogens. In virusinfected cells, RelA typically induces the expression of IFN-␤, which restrains viral propagation in neighboring cells involving paracrine mechanisms. Our study suggested that RelA might also play a proviral role. A cell-autonomous RelA activity amplified the yield of Chandipura virus, a cytopathic RNA virus associated with human epidemics, by extending the life span of infected cells. Our finding necessitates a substantial revision of our understanding of host-virus interactions and indicates a dual role of NF-B signaling during the course of RNA virus infections. Our study also bears significance for therapeutic regimes which alter NF-B activities while alleviating the viral load.

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Pathway‐extended gene expression signatures integrate novel biomarkers that improve predictions of patient responses to kinase inhibitors

Bagchee-Clark

Mucaki

Whitehead

et al. 2020

MedComm

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Cancer chemotherapy responses have been related to multiple pharmacogenetic biomarkers, often for the same drug. This study utilizes machine learning to derive multi‐gene expression signatures that predict individual patient responses to specific tyrosine kinase inhibitors, including erlotinib, gefitinib, sorafenib, sunitinib, lapatinib and imatinib. Support vector machine (SVM) learning was used to train mathematical models that distinguished sensitivity from resistance to these drugs using a novel systems biology‐based approach. This began with expression of genes previously implicated in specific drug responses, then expanded to evaluate genes whose products were related through biochemical pathways and interactions. Optimal pathway‐extended SVMs predicted responses in patients at accuracies of 70% (imatinib), 71% (lapatinib), 83% (sunitinib), 83% (erlotinib), 88% (sorafenib) and 91% (gefitinib). These best performing pathway‐extended models demonstrated improved balance predicting both sensitive and resistant patient categories, with many of these genes having a known role in cancer aetiology. Ensemble machine learning‐based averaging of multiple pathway‐extended models derived for an individual drug increased accuracy to >70% for erlotinib, gefitinib, lapatinib and sorafenib. Through incorporation of novel cancer biomarkers, machine learning‐based pathway‐extended signatures display strong efficacy predicting both sensitive and resistant patient responses to chemotherapy.

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Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway

Cited by 38 publications

References 51 publications

A TNF ‐p100 pathway subverts noncanonical NF ‐κB signaling in inflamed secondary lymphoid organs

A TNF ‐p100 pathway subverts noncanonical NF ‐κB signaling in inflamed secondary lymphoid organs

Chandipura Virus Utilizes the Prosurvival Function of RelA NF-κB for Its Propagation

Pathway‐extended gene expression signatures integrate novel biomarkers that improve predictions of patient responses to kinase inhibitors

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