Dataset Information

An NF?B Activity Calculator to Delineate Signaling Crosstalk: Type I and II Interferons Enhance NF?B via Distinct Mechanisms.

ABSTRACT: Nuclear factor kappa B (NF?B) is a transcription factor that controls inflammation and cell survival. In clinical histology, elevated NF?B activity is a hallmark of poor prognosis in inflammatory disease and cancer, and may be the result of a combination of diverse micro-environmental constituents. While previous quantitative studies of NF?B focused on its signaling dynamics in single cells, we address here how multiple stimuli may combine to control tissue level NF?B activity. We present a novel, simplified model of NF?B (SiMoN) that functions as an NF?B activity calculator. We demonstrate its utility by exploring how type I and type II interferons modulate NF?B activity in macrophages. Whereas, type I IFNs potentiate NF?B activity by inhibiting translation of I?B? and by elevating viral RNA sensor (RIG-I) expression, type II IFN amplifies NF?B activity by increasing the degradation of free I?B through transcriptional induction of proteasomal cap components (PA28). Both cross-regulatory mechanisms amplify NF?B activation in response to weaker (viral) inducers, while responses to stronger (bacterial or cytokine) inducers remain largely unaffected. Our work demonstrates how the NF?B calculator can reveal distinct mechanisms of crosstalk on NF?B activity in interferon-containing microenvironments.

SUBMITTER: Mitchell S

PROVIDER: S-EPMC6604663 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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An NFκB Activity Calculator to Delineate Signaling Crosstalk: Type I and II Interferons Enhance NFκB via Distinct Mechanisms.

Mitchell Simon S Mercado Ellen L EL Adelaja Adewunmi A Ho Jessica Q JQ Cheng Quen J QJ Ghosh Gourisankar G Hoffmann Alexander A

Frontiers in immunology 20190625

Nuclear factor kappa B (NFκB) is a transcription factor that controls inflammation and cell survival. In clinical histology, elevated NFκB activity is a hallmark of poor prognosis in inflammatory disease and cancer, and may be the result of a combination of diverse micro-environmental constituents. While previous quantitative studies of NFκB focused on its signaling dynamics in single cells, we address here how multiple stimuli may combine to control tissue level NFκB activity. We present a nove ...[more]

PMID: 31293585

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Project description:BackgroundSeven transmembrane receptors (7TMRs) can adopt different active conformations facilitating a selective activation of either G protein or ?-arrestin-dependent signaling pathways. This represents an opportunity for development of novel therapeutics targeting selective biological effects of a given receptor. Several studies on pathway separation have been performed, many of these on the Angiotensin II type 1 receptor (AT1R). It has been shown that certain ligands or mutations facilitate internalization and/or recruitment of ?-arrestins without activation of G proteins. However, the underlying molecular mechanisms remain largely unresolved. For instance, it is unclear whether such selective G protein-uncoupling is caused by a lack of ability to interact with G proteins or rather by an increased ability of the receptor to recruit ?-arrestins. Since uncoupling of G proteins by increased ability to recruit ?-arrestins could lead to different cellular or in vivo outcomes than lack of ability to interact with G proteins, it is essential to distinguish between these two mechanisms.Methodology/principal findingsWe studied five AT1R mutants previously published to display pathway separation: D74N, DRY/AAY, Y292F, N298A, and Y302F (Ballesteros-Weinstein numbering: 2.50, 3.49-3.51, 7.43, 7.49, and 7.53). We find that D74N, DRY/AAY, and N298A mutants are more prone to ?-arrestin recruitment than WT. In contrast, receptor mutants Y292F and Y302F showed impaired ability to recruit ?-arrestin in response to Sar1-Ile4-Ile8 (SII) Ang II, a ligand solely activating the ?-arrestin pathway.Conclusions/significanceOur analysis reveals that the underlying conformations induced by these AT1R mutants most likely represent principally different mechanisms of uncoupling the G protein, which for some mutants may be due to their increased ability to recruit ?-arrestin2. Hereby, these findings have important implications for drug discovery and 7TMR biology and illustrate the necessity of uncovering the exact molecular determinants for G protein-coupling and ?-arrestin recruitment, respectively.

Project description:Intraperitoneal metastasis is a common occurrence and is usually involved in the poor prognosis of ovarian cancer. Its specific metastatic pattern implies that certain indispensable microenvironmental factors secreted in the peritoneal cavity can direct metastatic ovarian cancer cells to permissive niches for secondary lesion formation. However, the underlying molecular mechanisms are ill defined. Herein, we report that GRO-α and IL-8 are predominately upregulated in culture media derived from either normal or cancerous omenta and are associated with increased ovarian cancer aggressiveness. Methods: OCM was established from culture medium of fresh human omental tissues. Primary and metastatic ovarian cancer cell lines were generated from human tumor tissues and verified by specific antibodies. The functional roles of GRO-α, IL-8, and their specific receptor CXCR2 were examined by neutralizing antibodies, shRNA gene knockdown, CRISPR/Cas9 gene knockout and pharmaceutical CXCR2 inhibitor SB225002. The oncogenic properties of ovarian cancer cells were examined by in vitro and in vivo mouse models. Results: Both GRO-α and IL-8 can activate TAK1/NFκB signaling via the CXCR2 receptor. Intriguingly, TAK1/NFκB signaling activity was higher in metastatic ovarian cancer cells; this higher activity makes them more susceptible to OCM-induced tumor aggressiveness. Treatment of ovarian cancer cells with GRO-α and IL-8 neutralizing antibodies or ablation of CXCR2 by shRNA gene knockdown, CRISPR/Cas9 gene knockout, or CXCR2 inhibitor SB225002 treatment significantly attenuated TAK1/NFκB signaling and decreased in vitro and in vivo oncogenic and metastatic potential, suggesting CXCR2 plays a key role in the GRO-α and IL-8-governed metastatic spreading of ovarian cancer cells in the intraperitoneal cavity. Conclusion: This study highlights the significance of GRO-α and IL-8 as the key chemokines in the peritoneal tumor microenvironment and suggests the utility of targeting their receptor CXCR2 as a potential target-based therapy for peritoneal metastases of ovarian cancer.

Dataset Information

An NF?B Activity Calculator to Delineate Signaling Crosstalk: Type I and II Interferons Enhance NF?B via Distinct Mechanisms.

Publications

An NFκB Activity Calculator to Delineate Signaling Crosstalk: Type I and II Interferons Enhance NFκB via Distinct Mechanisms.

Similar Datasets

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