BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL2207210003?filename=Trares2022%20-%20Crosstalk%20between%20the%20canonical%20and%20non-canonical%20NF-kB%20pathways%20-%20Petri%20net.xmlprimary200OKAnn-Kathrin OttoNon-curatedpetri netL3V1https://www.ebi.ac.uk/biomodels/MODEL220721000334688841falseBioModelsSBMLModelsTrares2022 Crosstalk between the canonical and non canonical NF kB pathways, Petri net2022MODEL2207210003Kira Trares, Jörg Ackermann, Ina KochKira Trares34688841, NF-κB is a protein complex that occurs in almost all animal cell types. It regulates the cellular immune responses to stimuli in the nucleus. Dysregulation of NF-κB can cause severe diseases like chronic inflammation, autoimmune diseases or cancer. We modeled the two major pathways leading from the external cellular stimulation of the CD40 receptor to the nuclear translocation of NF-κB dimers, the canonical and non-canonical pathway. Based on literature data, we developed two Petri net models describing these pathways. In a third Petri net, we combined the two models, introducing crosstalk specific in CD40L-stimulated B cells. In terms of structural properties, we checked the Petri nets for their consistency and correctness. To explore differences and similarities, we compared structural properties and the simulation behavior of the models. The non-canonical NF-κB pathway exhibited a more diverse regulation than the canonical pathway. Applying in silico knockout analyses, we were able to quantify the relevance of individual biochemical processes. We predicted interrelationships, e.g., between the synthesis of the protein NF-κB-inducing kinase and the processing of the precursor protein p100. The activation of the transcription factors, p50-RelA and p52-RelB, was affected by most of the knockouts. The results of the in silico knockout were in accordance with experimental studies. The Petri net models provide a basis for further analyses and could be extended to include gene expression, additional pathways, molecular processes, and kinetic data.. null, 211. Network Aging Research, Heidelberg University, Bergheimer Straße 20, 69115, Heidelberg, Germany; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.annkathrin.otto1@gmail.comGoethe University FrankfurtProcessing of the nf(kappa)b2 gene product p100 to generate p52 is an important step in NF-kappaB regulation. We show that this step is negatively regulated by a processing-inhibitory domain (PID) within p100 and positively regulated by the NF-kappaB-inducing kinase (NIK). While the PID suppresses the constitutive processing of p100, NIK induces p100 processing by stimulating site-specific phosphorylation and ubiquitination of this precursor protein. Further, a natural mutation of the gene encoding NIK in alymphoplasia (aly) mice cripples the function of NIK in p100 processing, causing a severe defect in p52 production. These data suggest that NIK is a specific kinase regulating p100 processing and explain why the aly and nf(kappa)b2 knockout mice exhibit similar immune deficiencies.The NF-kappaB-inducing kinase (NIK) induces proteolytic processing of NF-kappaB2/p100 and, hence, the generation of NF-kappaB dimers such as p52:RelB but was suggested not to signal for the processing of IkappaB. Here, we show that although the induction of IkappaB degradation in lymphocytes by TNF is independent of NIK, its induction by CD70, CD40 ligand, and BLyS/BAFF, which all also induce NF-kappaB2/p100 processing, does depend on NIK function. Both CD70 and TNF induce recruitment of the IKK kinase complex to their receptors. In the case of CD70, but not TNF, this process is associated with NIK recruitment and is followed by prolonged receptor association of just IKK1 and NIK. Recruitment of the IKK complex to CD27, but not that of NIK, depends on NIK kinase function. Our findings indicate that NIK participates in a unique set of proximal signaling events initiated by specific inducers, which activate both canonical and noncanonical NF-kappaB dimers.The adaptor and signaling proteins TRAF2, TRAF3, cIAP1 and cIAP2 may inhibit alternative nuclear factor-kappaB (NF-kappaB) signaling in resting cells by targeting NF-kappaB-inducing kinase (NIK) for ubiquitin-dependent degradation, thus preventing processing of the NF-kappaB2 precursor protein p100 to release p52. However, the respective functions of TRAF2 and TRAF3 in NIK degradation and activation of alternative NF-kappaB signaling have remained elusive. We now show that CD40 or BAFF receptor activation result in TRAF3 degradation in a cIAP1-cIAP2- and TRAF2-dependent way owing to enhanced cIAP1, cIAP2 TRAF3-directed ubiquitin ligase activity. Receptor-induced activation of cIAP1 and cIAP2 correlated with their K63-linked ubiquitination by TRAF2. Degradation of TRAF3 prevented association of NIK with the cIAP1-cIAP2-TRAF2 ubiquitin ligase complex, which resulted in NIK stabilization and NF-kappaB2-p100 processing. Constitutive activation of this pathway causes perinatal lethality and lymphoid defects.The noncanonical nuclear factor-κB (NF-κB) signaling pathway mediates activation of the p52/RelB NF-κB complex and, thereby, regulates specific immunological processes. This NF-κB pathway relies on the inducible processing of NF-κB2 precursor protein, p100, as opposed to the degradation of IκBα in the canonical NF-κB pathway. A central signaling component of the noncanonical NF-κB pathway is NF-κB-inducing kinase (NIK), which functions together with a downstream kinase, IKKα (inhibitor of NF-κB kinase α), to induce phosphorylation-dependent ubiquitination and processing of p100. Under normal conditions, NIK is targeted for continuous degradation by a tumor necrosis factor (TNF) receptor-associated factor-3 (TRAF3)-dependent E3 ubiquitin ligase. In response to signals mediated by a subset of TNF receptor superfamily members, NIK becomes stabilized as a result of TRAF3 degradation, leading to the activation of noncanonical NF-κB. This review discusses both the historical perspectives and the recent progress in the regulation and biological function of the noncanonical NF-κB pathway.The non-canonical NF-κB pathway forms a major arm of NF-κB signalling that mediates important biological functions, including lymphoid organogenesis, B-lymphocyte function, and cell growth and survival. Activation of the non-canonical NF-κB pathway involves degradation of an inhibitory protein, TNF receptor-associated factor 3 (TRAF3), but how this signalling event is controlled is still unknown. Here we have identified the deubiquitinase OTUD7B as a pivotal regulator of the non-canonical NF-κB pathway. OTUD7B deficiency in mice has no appreciable effect on canonical NF-κB activation but causes hyperactivation of non-canonical NF-κB. In response to non-canonical NF-κB stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-κB activation. Consequently, the OTUD7B deficiency results in B-cell hyper-responsiveness to antigens, lymphoid follicular hyperplasia in the intestinal mucosa, and elevated host-defence ability against an intestinal bacterial pathogen, Citrobacter rodentium. These findings establish OTUD7B as a crucial regulator of signal-induced non-canonical NF-κB activation and indicate a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3.Immunoglobulin class switching is crucial for the generation of antibody diversity in humoral immunity and, when deregulated, also has severe pathological consequences. How the magnitude of immunoglobulin isotype switching is controlled is still poorly understood. Here we identify the kinase TBK1 as a pivotal negative regulator of class switching to the immunoglobulin A (IgA) isotype. B cell-specific ablation of TBK1 in mice resulted in uncontrolled production of IgA and the development of nephropathy-like disease signs. TBK1 negatively regulated IgA class switching by attenuating noncanonical signaling via the transcription factor NF-κB, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase NIK. Our findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and identify a unique mechanism that controls IgA production.Two members of the NF-kappaB (nuclear factor kappaB)/Rel transcription factor family, NF-kappaB1 and NF-kappaB2, are produced as precursor proteins, NF-kappaB1 p105 and NF-kappaB2 p100 respectively. These are proteolytically processed by the proteasome to produce the mature transcription factors NF-kappaB1 p50 and NF-kappaB2 p52. p105 and p100 are known to function additionally as IkappaBs (inhibitors of NF-kappaB), which retain associated NF-kappaB subunits in the cytoplasm of unstimulated cells. The present review focuses on the latest advances in research on the function of NF-kappaB1 and NF-kappaB2 in immune cells. NF-kappaB2 p100 processing has recently been shown to be stimulated by a subset of NF-kappaB inducers, including lymphotoxin-beta, B-cell activating factor and CD40 ligand, via a novel signalling pathway. This promotes the nuclear translocation of p52-containing NF-kappaB dimers, which regulate peripheral lymphoid organogenesis and B-lymphocyte differentiation. Increased p100 processing also contributes to the malignant phenotype of certain T- and B-cell lymphomas. NF-kappaB1 has a distinct function from NF-kappaB2, and is important in controlling lymphocyte and macrophage function in immune and inflammatory responses. In contrast with p100, p105 is constitutively processed to p50. However, after stimulation with agonists, such as tumour necrosis factor-alpha and lipopolysaccharide, p105 is completely degraded by the proteasome. This releases associated p50, which translocates into the nucleus to modulate target gene expression. p105 degradation also liberates the p105-associated MAP kinase (mitogen-activated protein kinase) kinase kinase TPL-2 (tumour progression locus-2), which can then activate the ERK (extracellular-signal-regulated kinase)/MAP kinase cascade. Thus, in addition to its role in NF-kappaB activation, p105 functions as a regulator of MAP kinase signalling.Thymic epithelial cells (TECs) provide the microenvironment required for the development of T cells in the thymus. A unique property of medullary thymic epithelial cells (mTECs) is their expression of a wide range of tissue-restricted self-antigens, critically regulated by the nuclear protein AIRE, which contributes to the selection of the self-tolerant T cell repertoire, thereby suppressing the onset of autoimmune diseases. The TNF receptor family (TNFRF) protein receptor activator of NF-κB (RANK), CD40 and lymphotoxin β receptor (LtβR) regulate the development and functions of mTECs. The engagement of these receptors with their specific ligands results in the activation of the NF-κB family of transcription factors. Two NF-κB activation pathways, the classical and non-classical pathways, promote the development of mature mTECs induced by these receptors. Consistently, TNF receptor-associated factor (TRAF6), the signal transducer of the classical pathway, and NF-κB inducing kinase (NIK), the signal transducer of the non-classical pathway, are essential for the development of mature mTECs. This review summarizes the current understanding of how the signaling by the TNF receptor family controls the development and functions of mTEC.Processing of the NF-kappaB2 precursor protein p100 is a major step in noncanonical NF-kappaB signaling. This signaling step requires the NF-kappaB inducing kinase (NIK) and its downstream kinase, IkappaB kinase alpha (IKKalpha). We show here that p100 undergoes phosphorylation at serines 866, 870, and possibly 872, in cells stimulated with noncanonical NF-kappaB stimuli or transfected with NIK and IKKalpha. Phosphorylation of this serine cluster creates a binding site for beta-TrCP, the receptor subunit of the beta-TrCP(SCF) ubiquitin ligase. Mutation of either serine 866 or serine 870 abolishes the beta-TrCP recruitment and ubiquitination of p100. The functional significance of p100 phosphorylation is further supported by the finding that this molecular event occurs in a NIK- and IKKalpha-dependent manner. Additionally, induction of p100 phosphorylation can be blocked by a protein synthesis inhibitor, suggesting the requirement of de novo protein synthesis. These data suggest that p100 processing involves its phosphorylation at specific terminal serines, which form a binding site for beta-TrCP thereby regulating p100 ubiquitination.<h4>Aims</h4>Nuclear factor kappa light chain enhancer of activated B cells (NFkB) is a ubiquitous transcription factor well known for its role in the innate immune response. As such, NFkB is a transcriptional activator of inflammatory mediators such as cytokines. It has recently been demonstrated that alcohol and other drugs of abuse can induce NFkB activity and cytokine expression in the brain. A number of reviews have been published highlighting this effect of alcohol, and have linked increased NFkB function to neuroimmune-stimulated toxicity. However, in this review we focus on the potentially non-immune functions of NFkB as possible links between NFkB and addiction.<h4>Methods</h4>An extensive review of the literature via Pubmed searches was used to assess the current state of the field.<h4>Results</h4>NFkB can induce the expression of a diverse set of gene targets besides inflammatory mediators, some of which are involved in addictive processes, such as opioid receptors and neuropeptides. NFkB mediates complex behaviors including learning and memory, stress responses, anhedonia and drug reward, processes that may lie outside the role of NFkB in the classic neuroimmune response.<h4>Conclusions</h4>Future studies should focus on these non-immune functions of NFkB signaling and their association with addiction-related processes.This article serves as an introduction to the collection of reviews on nuclear factor-kappaB (NF-kappaB). It provides an overview of the discovery and current status of NF-kappaB as a research topic. Described are the structures, activities and regulation of the proteins in the NF-kappaB family of transcription factors. NF-kappaB signaling is primarily regulated by inhibitor kappaB (IkappaB) proteins and the IkappaB kinase complex through two major pathways: the canonical and non-canonical NF-kappaB pathways. The organization and focus of articles included in the following reviews are described, as well as likely future areas of research interest on NF-kappaB.The past two decades have led to a tremendous work on the transcription factor NF-kappaB and its molecular mechanisms of activation. The nuclear translocation of NF-kappaB is controlled by two main pathways: the classical and the alternative NF-kappaB pathways. The classical NF-kappaB pathway activates the IKK complex that controls the inducible degradation of most IkappaB family members that are IkappaBalpha, IkappaBbeta, IkappaBvarepsilon and p105. The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. Genetic studies have shown that IKKgamma is dispensable for the alternative pathway, which suggests the existence of an alternative IKKalpha-containing complex. It is noteworthy that activation of particular p52 heterodimers like p52/RelB requires solely the alternative pathway while activation of p52/p65 or p52/c-Rel involves a "hybrid pathway". Among others, LTbetaR, BAFF-R, CD40 and RANK have the ability to induce the alternative pathway. The latter plays some roles in biological functions controlled by these receptors, which are the development of secondary lymphoid organs, the proliferation, survival and maturation of B cell, and the osteoclastogenesis. Exacerbated activation of the alternative pathway is potentially associated to a wide range of disorders like rheumatoid arthritis, ulcerative colitis or B cell lymphomas. Therefore, inhibitors of the alternative pathway could be valuable tools for the treatment of inflammatory disorders and cancers.CD40-induced signalling through ligation with its natural ligand (CD40L/CD154) is dependent on recruitment of TRAF molecules to the cytoplasmic domain of the receptor. Here, we applied the yeast two-hybrid system to examine whether other proteins can interact with CD40. Fas-Associated Factor 1(FAF1) was isolated from a HeLa cDNA library using the CD40 cytoplasmic tail (216-278 aa) as a bait construct. FAF1 was able to interact with CD40 both in vitro and in vivo. The FAF1 N-terminal domain was sufficient to bind CD40 and required the TRAF6-binding domain within the cytoplasmic tail of CD40 for binding. CD40 ligation induced FAF1 expression in an NFκB-dependent manner. Knockdown of FAF1 prolonged CD40-induced NFκB, whereas overexpression of FAF1 suppressed CD40-induced NFκB activity and this required interaction of FAF1 with the CD40 receptor via its FID domain. Thus, we report a novel role for FAF1in regulating CD40-induced NFκB activation via a negative feedback loop. Loss of FAF1 function in certain human malignancies may contribute to oncogenesis through unchecked NFκB activation, and further understanding of this process may provide a biomarker of NFκB-targeted therapies for such malignancies.The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies.The transcription factor NF-kappaB has been the focus of intense investigation for nearly two decades. Over this period, considerable progress has been made in determining the function and regulation of NF-kappaB, although there are nuances in this important signaling pathway that still remain to be understood. The challenge now is to reconcile the regulatory complexity in this pathway with the complexity of responses in which NF-kappaB family members play important roles. In this review, we provide an overview of established NF-kappaB signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-kappaB transcriptional activity.The transcription factor NF-kappaB is a tightly regulated positive mediator of T- and B-cell development, proliferation, and survival. The controlled activity of NF-kappaB is required for the coordination of physiologic immune responses. However, constitutive NF-kappaB activation can promote continuous lymphocyte proliferation and survival and has recently been recognized as a critical pathogenetic factor in lymphoma. Various molecular events lead to deregulation of NF-kappaB signaling in Hodgkin disease and a variety of T- and B-cell non-Hodgkin lymphomas either up-stream or downstream of the central IkappaB kinase. These alterations are prerequisites for lymphoma cell cycling and blockage of apoptosis. This review provides an overview of the NF-kappaB pathway and discusses the mechanisms of NF-kappaB deregulation in distinct lymphoma entities with defined aberrant pathways: Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), mucosa-associated lymphoid tissue (MALT) lymphoma, primary effusion lymphoma (PEL), and adult T-cell lymphoma/leukemia (ATL). In addition, we summarize recent data that validates the NF-kappaB signaling pathway as an attractive therapeutic target in T- and B-cell malignancies.IkappaB [inhibitor of nuclear factor kappaB (NF-kappaB)] kinase (IKK) phosphorylates IkappaB inhibitory proteins, causing their degradation and activation of transcription factor NF-kappaB, a master activator of inflammatory responses. IKK is composed of three subunits-IKKalpha and IKKbeta, which are highly similar protein kinases, and IKKgamma, a regulatory subunit. In mammalian cells, phosphorylation of two sites at the activation loop of IKKbeta was essential for activation of IKK by tumor necrosis factor and interleukin-1. Elimination of equivalent sites in IKKalpha, however, did not interfere with IKK activation. Thus, IKKbeta, not IKKalpha, is the target for proinflammatory stimuli. Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.NF-κB is a protein complex that occurs in almost all animal cell types. It regulates the cellular immune responses to stimuli in the nucleus. Dysregulation of NF-κB can cause severe diseases like chronic inflammation, autoimmune diseases or cancer. We modeled the two major pathways leading from the external cellular stimulation of the CD40 receptor to the nuclear translocation of NF-κB dimers, the canonical and non-canonical pathway. Based on literature data, we developed two Petri net models describing these pathways. In a third Petri net, we combined the two models, introducing crosstalk specific in CD40L-stimulated B cells. In terms of structural properties, we checked the Petri nets for their consistency and correctness. To explore differences and similarities, we compared structural properties and the simulation behavior of the models. The non-canonical NF-κB pathway exhibited a more diverse regulation than the canonical pathway. Applying in silico knockout analyses, we were able to quantify the relevance of individual biochemical processes. We predicted interrelationships, e.g., between the synthesis of the protein NF-κB-inducing kinase and the processing of the precursor protein p100. The activation of the transcription factors, p50-RelA and p52-RelB, was affected by most of the knockouts. The results of the in silico knockout were in accordance with experimental studies. The Petri net models provide a basis for further analyses and could be extended to include gene expression, additional pathways, molecular processes, and kinetic data.Functions of NF-kappaB1 and NF-kappaB2 in immune cell biology.Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications.Fas-associated factor (Faf1) is a novel CD40 interactor that regulates CD40-induced NF-κB activation via a negative feedback loop.beta-TrCP binding and processing of NF-kappaB2/p100 involve its phosphorylation at serines 866 and 870.Non-canonical NF-κB signaling pathway.The noncanonical NF-κB pathway.NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100.The non-canonical NF-κB pathway in immunity and inflammation.Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling.TNF receptor family signaling in the development and functions of medullary thymic epithelial cells.The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development.OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3.Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation.Introduction to NF-kappaB: players, pathways, perspectives.The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling.Signaling to NF-kappaB.The canonical and non-canonical NF-κB pathways and their crosstalk: A comparative study based on Petri nets.Receptor-specific signaling for both the alternative and the canonical NF-kappaB activation pathways by NF-kappaB-inducing kinase.The Role of NFkB in Drug Addiction: Beyond Inflammation.Liang Chunyang C, Zhang Minying M, Sun Shao-Cong SCRamakrishnan Parameswaran P, Wang Wangxia W, Wallach David DTrares Kira K, Ackermann Jörg J, Koch Ina IGilmore T D TDHayden Matthew S MS, Ghosh Sankar SElmetwali T T, Young L S LS, Palmer D H DHXiao G G, Harhaj E W EW, Sun S C SCJost Philipp J PJ, Ruland Jürgen JSun Shao-Cong SCDejardin Emmanuel EHu Hongbo H, Brittain George C GC, Chang Jae-Hoon JH, Puebla-Osorio Nahum N, Jin Jin J, Zal Anna A, Xiao Yichuan Y, Cheng Xuhong X, Chang Mikyoung M, Fu Yang-Xin YX, Zal Tomasz T, Zhu Chengming C, Sun Shao-Cong SCVallabhapurapu Sivakumar S, Matsuzawa Atsushi A, Zhang Weizhou W, Tseng Ping-Hui PH, Keats Jonathan J JJ, Wang Haopeng H, Vignali Dario A A DA, Bergsagel P Leif PL, Karin Michael MAkiyama Taishin T, Shinzawa Miho M, Akiyama Nobuko NDelhase M M, Hayakawa M M, Chen Y Y, Karin M MJin Jin J, Xiao Yichuan Y, Chang Jae-Hoon JH, Yu Jiayi J, Hu Hongbo H, Starr Robyn R, Brittain George C GC, Chang Mikyoung M, Cheng Xuhong X, Sun Shao-Cong SCNennig S E SE, Schank J R JRBeinke Sören S, Ley Steven C SCfalseTrares2022 - Crosstalk between the canonical and non-canonical NF-kB pathways, Petri netNo description2022-07-212022-07-222022-07-21MODEL2207210003SBO:0000393SBO:0000177SBO:0000394ENSG0000010101734688841224355512302339315214841169709251630328811239468211737961548562628580957229697702481004917119127170723211537133410195894280439691899779223334419Q13489Q13490P29965Q13114Q01201Q00653Q9Y4K3Q12933O14920O15111Q9Y6K9O43318Q6GQQ9Q04206P19838Q99558P25963Q9UHD2