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Simon2019 - NIK-dependent p100 processing into p52, Mass Action, SBML 2v4

ABSTRACT: This model represents NIK-dependent p100 processing into p52 with mass action kinetics. While this model shows identical dose-response to the Michaelis-Menten representation, when IkBd degradation is included the dose-response is no longer monotonic in mass action models due to substrate complex competition.

SUBMITTER: Simon Mitchell

PROVIDER: BIOMD0000000868 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000868?filename=MA-p52.xml	Xml
	BIOMD0000000868?filename=simon2019_model2.cps	Other
	BIOMD0000000868?filename=simon2019_model2.sedml	Other
	BIOMD0000000868?filename=simon2019_model2.xml	Xml

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Publications

Substrate complex competition is a regulatory motif that allows NFκB RelA to license but not amplify NFκB RelB.

Mitchell Simon S Hoffmann Alexander A

Proceedings of the National Academy of Sciences of the United States of America 20190502 21

Signaling pathways often share molecular components, tying the activity of one pathway to the functioning of another. In the NFκB signaling system, distinct kinases mediate inflammatory and developmental signaling via RelA and RelB, respectively. Although the substrates of the developmental, so-called noncanonical, pathway are induced by inflammatory/canonical signaling, crosstalk is limited. Through dynamical systems modeling, we identified the underlying regulatory mechanism. We found that as ...[more]

PMID: 31048505

Similar Datasets

Simon2019 - NIK-dependent p100 processing into p52, Michaelis-Menten, SBML 2v4

Project description:This model represents NIK-dependent p100 processing into p52 with Michaelis-Menten kinetics. While this model shows identical dose-response to the mass action representation, when IkBd degradation is included the dose-response is no-longer monotonic in mass action models due to substrate complex competition.

2024-09-02 | BIOMD0000000866 | BioModels

Simon2019 - NIK-dependent p100 processing into p52 and IkBd degradation, mass action, SBML 2v4

Project description:This model represents NIK-dependent p100 processing into p52 and NIK-dependent IkBd degradation with mass action kinetics. Compare this mass action representation to the Michaelis-Menten model. In this model the dose-response to increasing p100 mRNA is not monotonic due to substrate complex competition.

2024-09-02 | BIOMD0000000870 | BioModels

Simon2019 - NIK-dependent p100 processing into p52 and IkBd degradation, Michaelis-Menten, SBML 2v4

Project description:This model represents NIK-dependent p100 processing into p52 and NIK-dependent IkBd degradation with Michaelis-Menten kinetics. Compare this Michaelis-Menten representation to the mass action model in which the dose-response to increasing p100 mRNA is no longer monotonic due to substrate complex competition.

2024-09-02 | BIOMD0000000869 | BioModels

NIK-dependent p100 processing into p52 with RelB binding and IkBd degradation, mass action, SBML 2v4

Project description:This model represents NIK-dependent p100 processing into p52 followed by binding to RelB and NIK-dependent IkBd degradation. This model assesses the impact of substrate complex competition on RelB-p52.

2024-09-02 | BIOMD0000000871 | BioModels

Balance between NF-κB p100 and p52 regulates T cell costimulation dependence.

Project description:c-IAP1 and c-IAP2 are ubiquitin protein ligases (E3s) that repress noncanonical NF-κB activation. We have created mice that bear a mutation in c-IAP2 that inactivates its E3 activity and interferes, in a dominant-negative fashion, with c-IAP1 E3 activity (c-IAP2(H570A)). The immune response of these animals was explored by infecting them with the Th1-inducing parasite Toxoplasma gondii. Surprisingly, c-IAP2(H570A) mice succumbed because of T cell production of high levels of proinflammatory cytokines. Unlike naive wild-type (WT) cells, which require signals generated by the TCR and costimulatory receptors to become fully activated, naive c-IAP2(H570A) T cells proliferated and produced high levels of IL-2 and IFN-γ to stimulation via TCR alone. c-IAP2(H570A) T cells had constitutive noncanonical NF-κB activation, and IκB kinase inhibition reduced their proliferation to anti-TCR alone to WT levels but had no effect when costimulation via CD28 was provided. Notably, T cells from nfkb2(-/-) mice, which cannot generate the p52 component of noncanonical NF-κB, were also costimulation independent, consistent with the negative role of this unprocessed protein in canonical NF-κB activation. Whereas T cells from nfkb2(+/-) mice behaved like WT, coexpression of a single copy of c-IAP2(H570A) resulted in cleavage of p100, upregulation of p52, and T cell costimulation independence. Thus, p100 represses and p52 promotes costimulation, and the ratio regulates T cell dependence on costimulatory signals.

| S-EPMC3538904 | biostudies-literature

TRIM14 Promotes Noncanonical NF-κB Activation by Modulating p100/p52 Stability via Selective Autophagy.

Project description:The noncanonical NF-κB signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF-κB signaling largely relies on the abundance as well as the processing of the NF-κB family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF-κB signaling pathway. TRIM14 promotes noncanonical NF-κB activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63-linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62-mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF-κB-mediated inflammatory responses as well as acute colitis and colitis-associated colon cancer development. Taken together, these findings establish the TRIM14-USP14 axis as a crucial checkpoint that controls noncanonical NF-κB signaling and highlight the crosstalk between autophagy and innate immunity.

| S-EPMC6947505 | biostudies-literature

Crotonylation sensitizes IAPi-induced disruption of latent HIV by enhancing p100 cleavage into p52.

Project description:The eradication of HIV infection is difficult to achieve because of stable viral reservoirs. Here, we show that crotonylation enhances AZD5582-induced noncanonical NF-κB (ncNF-κB) signaling, further augmenting HIV latency reversal in Jurkat and U1 cell line models of latency, HIV latently infected primary CD4+ T cells and resting CD4+ T cells isolated from people living with HIV. Crotonylation upregulated the levels of the active p52 subunit of NF-κB following AZD5582. Biochemical analyses suggest that the ubiquitin E3 ligase TRIM27 is involved in enhanced p100 cleavage to p52. When TRIM27 was depleted, AZD5582-induced HIV latency reversal was reduced. TRIM27 small interfering RNA (siRNA) knockdown reduced both p100 and p52 levels without inhibiting p100 transcription, indicating that TRIM27 not only acts on p100 cleavage but also may impact p100/p52 stability. These observations reveal the complexity of HIV transcriptional machinery, particularly of NF-κB.

| S-EPMC8728431 | biostudies-literature

Noncanonical NF-κB factor p100/p52 regulates homologous recombination and modulates sensitivity to DNA-damaging therapy.

Project description:Homologous recombination (HR) serves multiple roles in DNA repair that are essential for maintaining genomic stability, including double-strand DNA break (DSB) repair. The central HR protein, RAD51, is frequently overexpressed in human malignancies, thereby elevating HR proficiency and promoting resistance to DNA-damaging therapies. Here, we find that the non-canonical NF-κB factors p100/52, but not RelB, control the expression of RAD51 in various human cancer subtypes. While p100/p52 depletion inhibits HR function in human tumor cells, it does not significantly influence the proficiency of non-homologous end joining, the other key mechanism of DSB repair. Clonogenic survival assays were performed using a pair DLD-1 cell lines that differ only in their expression of the key HR protein BRCA2. Targeted silencing of p100/p52 sensitizes the HR-competent cells to camptothecin, while sensitization is absent in HR-deficient control cells. These results suggest that p100/p52-dependent signaling specifically controls HR activity in cancer cells. Since non-canonical NF-κB signaling is known to be activated after various forms of genomic crisis, compensatory HR upregulation may represent a natural consequence of DNA damage. We propose that p100/p52-dependent signaling represents a promising oncologic target in combination with DNA-damaging treatments.

| S-EPMC9226503 | biostudies-literature

SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing.

Project description:A primary step in activating the alternative nuclear factor-kappaB (NF-kappaB) pathway requires NF-kappaB2/p100 processing to generate p52. In most cases, stimuli-induced p100 processing is dependent on NF-kappaB-inducing kinase/IkappaB kinase alpha-mediated phosphorylation and ubiquitination. Here, we report that post-translational modification of p100 at specific sites by the small ubiquitin-like modifier (SUMO) is another determining factor for stimuli-induced p100 processing. The results show that basal SUMO modification is required for stimuli-induced p100 phosphorylation and that blocking SUMOylation of p100, either by site-directed mutation or by short interfering RNA-targeted diminution of E2 SUMO-conjugating enzyme Ubc9, inhibits various physiological stimuli-induced p100 processing and ultimate activation of the alternative NF-kappaB pathway. Together, these findings show the crucial role of SUMO1 modification in p100 processing and provide mechanistic insights into the participation of SUMO1 modification in the regulation of signal transduction.

| S-EPMC2529344 | biostudies-literature

Praziquantel mode of action and resistance

Project description:This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/The drug Praziquantel is the most commonly used drug for parasitic flatworms. It is currently being increasingly used in mass drug administration programmes, raising concerns over whether resistance will develop. Although widely used, its mode of action was until very recently uncertain. This study will investigate the praziquantel mode of action and resistance by sequencing the transcriptomes of Dugesia japonica and different stages and strains of S. mansoni.

2013-05-13 | E-ERAD-135 | biostudies-arrayexpress

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