{"database":"BioModels","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Xml":["https://www.ebi.ac.uk/biomodels/model/download/MODEL2210170001?filename=Amstein2022%20-%20TNFR1%20Signal%20Transduction%20-%20Petri%20Net.xml"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"submitter":["Ann-Kathrin Otto"],"curationStatus":["Non-curated"],"modellingApproach":["petri net"],"levelVersion":["L3V1"],"full_dataset_link":["https://www.ebi.ac.uk/biomodels/MODEL2210170001"],"publication_pubmed":["35994517"],"isPrivate":["false"],"repository":["BioModels"],"modelFormat":["SBML"],"omics_type":["Models"],"tokenised_name":["Amstein2022   TNFR1 Signal Transduction, Petri Net"],"publication_year":["2022"],"submissionId":["MODEL2210170001"],"publication_authors":["Leonie K Amstein, Jörg Ackermann, Jennifer Hannig, Ivan Đikić, Simone Fulda, Ina Koch"],"first_author":["Leonie K Amstein"],"publication":["35994517,\n                            The paper describes a mathematical model of the molecular switches of cell survival, apoptosis, and necroptosis in cellular signaling pathways initiated by tumor necrosis factor 1. Based on experimental findings in the literature, we constructed a Petri net model based on detailed molecular reactions of the molecular players, protein complexes, post-translational modifications, and cross talk. The model comprises 118 biochemical entities, 130 reactions, and 299 edges. We verified the model by evaluating invariant properties of the system at steady state and by in silico knockout analysis. Applying Petri net analysis techniques, we found 279 pathways, which describe signal flows from receptor activation to cellular response, representing the combinatorial diversity of functional pathways.120 pathways steered the cell to survival, whereas 58 and 35 pathways led to apoptosis and necroptosis, respectively. For 65 pathways, the triggered response was not deterministic and led to multiple possible outcomes. We investigated the in silico knockout behavior and identified important checkpoints of the TNFR1 signaling pathway in terms of ubiquitination within complex I and the gene expression dependent on NF-κB, which controls the caspase activity in complex II and apoptosis induction. Despite not knowing enough kinetic data of sufficient quality, we estimated system's dynamics using a discrete, semi-quantitative Petri net model.. 8, 18.\n                            Goethe University Frankfurt, Institute of Computer Science, Department of Molecular Bioinformatics, Frankfurt am Main, Germany."],"submitter_mail":["annkathrin.otto1@gmail.com"],"submitter_affiliation":["Goethe University Frankfurt"],"pubmed_abstract":["TNF is a key inflammatory cytokine. Using a modified tandem affinity purification approach, we identified HOIL-1 and HOIP as functional components of the native TNF-R1 signaling complex (TNF-RSC). Together, they were shown to form a linear ubiquitin chain assembly complex (LUBAC) and to ubiquitylate NEMO. We show that LUBAC binds to ubiquitin chains of different linkage types and that its recruitment to the TNF-RSC is impaired in TRADD-, TRAF2-, and cIAP1/2- but not in RIP1- or NEMO-deficient MEFs. Furthermore, the E3 ligase activity of cIAPs, but not TRAF2, is required for HOIL-1 recruitment to the TNF-RSC. LUBAC enhances NEMO interaction with the TNF-RSC, stabilizes this protein complex, and is required for efficient TNF-induced activation of NF-kappaB and JNK, resulting in apoptosis inhibition. Finally, we demonstrate that sustained stability of the TNF-RSC requires LUBAC's enzymatic activity, thereby adding a third form of ubiquitin linkage to the triggering of TNF signaling by the TNF-RSC.","IKKβ {IκB [inhibitor of NF-κB (nuclear factor κB)] kinase β} is required to activate the transcription factor NF-κB, but how IKKβ itself is activated in vivo is still unclear. It was found to require phosphorylation by one or more 'upstream' protein kinases in some reports, but by autophosphorylation in others. In the present study, we resolve this contro-versy by demonstrating that the activation of IKKβ induced by IL-1 (interleukin-1) or TNF (tumour necrosis factor) in embryonic fibroblasts, or by ligands that activate Toll-like receptors in macrophages, requires two distinct phosphorylation events: first, the TAK1 [TGFβ (transforming growth factor β)-activated kinase-1]-catalysed phosphorylation of Ser¹⁷⁷ and, secondly, the IKKβ-catalysed autophosphorylation of Ser¹⁸¹. The phosphorylation of Ser¹⁷⁷ by TAK1 is a priming event required for the subsequent autophosphorylation of Ser¹⁸¹, which enables IKKβ to phosphorylate exogenous substrates. We also provide genetic evidence which indicates that the IL-1-stimulated, LUBAC (linear ubiquitin chain assembly complex)-catalysed formation of linear ubiquitin chains and their interaction with the NEMO (NF-κB essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKβ at Ser¹⁷⁷ and IKKα at Ser¹⁷⁶. These findings may be of general significance for the activation of other protein kinases.","The paper describes a mathematical model of the molecular switches of cell survival, apoptosis, and necroptosis in cellular signaling pathways initiated by tumor necrosis factor 1. Based on experimental findings in the literature, we constructed a Petri net model based on detailed molecular reactions of the molecular players, protein complexes, post-translational modifications, and cross talk. The model comprises 118 biochemical entities, 130 reactions, and 299 edges. We verified the model by evaluating invariant properties of the system at steady state and by in silico knockout analysis. Applying Petri net analysis techniques, we found 279 pathways, which describe signal flows from receptor activation to cellular response, representing the combinatorial diversity of functional pathways.120 pathways steered the cell to survival, whereas 58 and 35 pathways led to apoptosis and necroptosis, respectively. For 65 pathways, the triggered response was not deterministic and led to multiple possible outcomes. We investigated the in silico knockout behavior and identified important checkpoints of the TNFR1 signaling pathway in terms of ubiquitination within complex I and the gene expression dependent on NF-κB, which controls the caspase activity in complex II and apoptosis induction. Despite not knowing enough kinetic data of sufficient quality, we estimated system's dynamics using a discrete, semi-quantitative Petri net model.","Caspase-8, the initiator caspase of the death receptor pathway of apoptosis, its adapter molecule, FADD, required for caspase-8 activation, and cFLIPL, a caspase-8-like protein that lacks a catalytic site and blocks caspase-8-mediated apoptosis, are each essential for embryonic development. Animals deficient in any of these genes present with E10.5 embryonic lethality. Recent studies have shown that development in caspase-8-deficient mice is rescued by ablation of RIPK3, a kinase that promotes a form of programmed, necrotic cell death. Here, we show that FADD, RIPK3 double-knockout mice develop normally but that the lethal effects of cFLIP deletion are not rescued by RIPK3 deficiency. Remarkably, in mice lacking FADD, cFLIP, and RIPK3, embryonic development is normal. This can be explained by the convergence of two cell processes: the enzymatic activity of the FADD-caspase-8-cFLIPL complex blocks RIPK3-dependent signaling (including necrosis), whereas cFLIPL blocks RIPK3-independent apoptosis promoted by the FADD-caspase-8 complex.","Programmed cell death plays critical roles in a wide variety of physiological processes during fetal development and in adult tissues. In most cases, physiological cell death occurs by apoptosis as opposed to necrosis. Defects in apoptotic cell death regulation contribute to many diseases, including disorders where cell accumulation occurs (cancer, restenosis) or where cell loss ensues (stroke, heart failure, neurodegeneration, AIDS). In recent years, the molecular machinery responsible for apoptosis has been elucidated, revealing a family of intracellular proteases, the caspases, which are responsible directly or indirectly for the morphological and biochemical changes that characterize the phenomenon of apoptosis. Diverse regulators of the caspases have also been discovered, including activators and inhibitors of these cell death proteases. Inputs from signal transduction pathways into the core of the cell death machinery have also been identified, demonstrating ways of linking environmental stimuli to cell death responses or cell survival maintenance. Knowledge of the molecular mechanisms of apoptosis is providing insights into the causes of multiple pathologies where aberrant cell death regulation occurs and is beginning to provide new approaches to the treatment of human diseases.","The intracellular regulation of cell death pathways by cIAPs has been enigmatic. Here we show that loss of cIAPs promotes the spontaneous formation of an intracellular platform that activates either apoptosis or necroptosis. This 2 MDa intracellular complex that we designate \"Ripoptosome\" is necessary but not sufficient for cell death. It contains RIP1, FADD, caspase-8, caspase-10, and caspase inhibitor cFLIP isoforms. cFLIP(L) prevents Ripoptosome formation, whereas, intriguingly, cFLIP(S) promotes Ripoptosome assembly. When cIAPs are absent, caspase activity is the \"rheostat\" that is controlled by cFLIP isoforms in the Ripoptosome and decides if cell death occurs by RIP3-dependent necroptosis or caspase-dependent apoptosis. RIP1 is the core component of the complex. As exemplified by our studies for TLR3 activation, our data argue that the Ripoptosome critically influences the outcome of membrane-bound receptor triggering. The differential quality of cell death mediated by the Ripoptosome may cause important pathophysiological consequences during inflammatory responses.","Cell death is critical to the normal functioning of multi-cellular organisms, playing a central role in development, immunity, inflammation, and cancer progression. Two cell death mechanisms, apoptosis and necroptosis, are dependent on the formation of distinct multi-protein complexes including the DISC, Apoptosome, Piddosome and Necrosome following the induction of cell death by specific stimuli. The role of several of these key multi-protein signalling platforms, namely the DISC, TNFR1 complex I/II, the Necrosome and Ripoptosome, in mediating these pathways will be discussed, as well as the open questions and potential therapeutic benefits of understanding their underlying mechanisms.","The realization that alterations in inhibitor of apoptosis (IAP) proteins are found in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis, has sparked a worldwide frenzy in the development of small pharmacological inhibitors of IAPs. The development of such inhibitors has radically changed our knowledge of the signalling processes that are regulated by IAPs. Recent studies indicate that IAPs not only regulate caspases and apoptosis, but also modulate inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis.","Receptor-interacting protein (RIP), a Ser/Thr kinase component of the tumor necrosis factor (TNF) receptor-1 signaling complex, mediates activation of the nuclear factor kappaB (NF-kappaB) pathway. RIP2 and RIP3 are related kinases that share extensive sequence homology with the kinase domain of RIP. Unlike RIP, which has a C-terminal death domain, and RIP2, which has a C-terminal caspase activation and recruitment domain, RIP3 possesses a unique C terminus. RIP3 binds RIP through this unique C-terminal segment to inhibit RIP- and TNF receptor-1-mediated NF-kappaB activation. We have identified a unique homotypic interaction motif at the C terminus of both RIP and RIP3 that is required for their association. Sixty-four amino acids within RIP3 and 88 residues within RIP are sufficient for interaction of the two proteins. This interaction is a prerequisite for RIP3-mediated phosphorylation of RIP and subsequent attenuation of TNF-induced NF-kappaB activation.","Caspase-8 has two opposing biological functions--it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T-lymphocyte activation, and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands. Here we show that development of caspase-8-deficient mice is completely rescued by ablation of receptor interacting protein kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand (also known as FAS and FASLG, respectively), and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIP(L), also known as CFLAR), and this complex is required for the protective function.","Apoptosis, or programmed cell death, plays a pivotal role in the elimination of unwanted, damaged, or infected cells in multicellular organisms and also in diverse biological processes, including development, cell differentiation, and proliferation. Apoptosis is a highly regulated form of cell death, and dysregulation of apoptosis results in pathological conditions including cancer, autoimmune and neurodegenerative diseases. The Bcl-2 family proteins are key regulators of apoptosis, which include both anti- and pro-apoptotic proteins, and a slight change in the dynamic balance of these proteins may result either in inhibition or promotion of cell death. Execution of apoptosis by various stimuli is initiated by activating either intrinsic or extrinsic pathways which lead to a series of downstream cascade of events, releasing of various apoptotic mediators from mitochondria and activation of caspases, important for the cell fate. In view of recent research advances about underlying mechanism of apoptosis, this review highlights the basics concept of apoptosis and its regulation by Bcl-2 family of protein. Furthermore, this review discusses the interplay of various apoptotic mediators and caspases to decide the fate of the cell. We expect that this review will add to the pool of basic information necessary to understand the mechanism of apoptosis which may implicate in designing better strategy to develop biomedical therapy to control apoptosis.","Cell death research was revitalized by the understanding that necrosis can occur in a highly regulated and genetically controlled manner. Although RIPK1 (receptor-interacting protein kinase 1)- and RIPK3-MLKL (mixed lineage kinase domain-like)-mediated necroptosis is the most understood form of regulated necrosis, other examples of this process are emerging, including cell death mechanisms known as parthanatos, oxytosis, ferroptosis, NETosis, pyronecrosis and pyroptosis. Elucidating how these pathways of regulated necrosis are interconnected at the molecular level should enable this process to be therapeutically targeted.","Inhibitor of Apoptosis Proteins (IAPs) can bind to and inhibit caspases, the key executioners of apoptosis. Because IAPs are frequently overexpressed in human tumors, they have become major pharmacological targets for developing new cancer therapeutics. However, the precise physiological function of individual mammalian IAPs and their role as E3 ubiquitin-ligases in situ remain largely obscure. Here, we investigated the function of XIAP ubiquitin-ligase activity by inactivating the RING motif via gene targeting in the mouse. Removing the RING stabilized XIAP in apoptotic thymocytes, demonstrating that XIAP ubiquitin-ligase activity is a major determinant of XIAP protein stability. Surprisingly, the increased amounts of \"XIAP-BIR-only\" protein did not lead to attenuated but rather increased caspase activity and apoptosis. DeltaRING embryonic stem cells and fibroblasts had elevated caspase-3 enzyme activity, and XIAP DeltaRING embryonic fibroblasts were strongly sensitized to TNF-alpha-induced apoptosis. Similar results were obtained with XIAP deficient mice. Furthermore, deletion of the RING also improved the survival of mice in the Emu-Myc lymphoma model. This demonstrates a physiological requirement of XIAP ubiquitin-ligase activity for the inhibition of caspases and for tumor suppression in vivo.","NF-kappaB transcription factors have key roles in inflammation, immune response, oncogenesis and protection against apoptosis. In most cells, these factors are kept inactive in the cytoplasm through association with IkappaB inhibitors. After stimulation by various reagents, IkappaB is phosphorylated by the IkappaB kinase (IKK) complex and degraded by the proteasome, allowing NF-kappaB to translocate to the nucleus and activate its target genes. Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis, interacts with NEMO, the regulatory subunit of IKK. CYLD also interacts directly with tumour-necrosis factor receptor (TNFR)-associated factor 2 (TRAF2), an adaptor molecule involved in signalling by members of the family of TNF/nerve growth factor receptors. CYLD has deubiquitinating activity that is directed towards non-K48-linked polyubiquitin chains, and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process. Truncations of CYLD found in cylindromatosis result in reduced enzymatic activity, indicating a link between impaired deubiquitination of CYLD substrates and human pathophysiology.","Programmed necrotic cell death induced by the tumor necrosis factor alpha (TNF-α) family of cytokines is dependent on a kinase cascade consisting of receptor-interacting kinases RIP1 and RIP3. How these kinase activities cause cells to die by necrosis is not known. The mixed lineage kinase domain-like protein MLKL is a functional RIP3 substrate that binds to RIP3 through its kinase-like domain but lacks kinase activity of its own. RIP3 phosphorylates MLKL at the T357 and S358 sites. Reported here is the development of a monoclonal antibody that specifically recognizes phosphorylated MLKL in cells dying of this pathway and in human liver biopsy samples from patients suffering from drug-induced liver injury. The phosphorylated MLKL forms an oligomer that binds to phosphatidylinositol lipids and cardiolipin. This property allows MLKL to move from the cytosol to the plasma and intracellular membranes, where it directly disrupts membrane integrity, resulting in necrotic death.","The Bcl-2 family protein Bax is a key effector of apoptosis. Lovell et al. (2008) now describe the reconstitution and regulation in liposomes of tBid-mediated membrane penetration and oligomerization of Bax. These and other recent studies shed new light on the control of permeabilization of the mitochondrial outer membrane during apoptosis.","Activation of the transcription factor NF-kappaB is a major effector of the inducible resistance to death receptor-mediated apoptosis. Previous evidence indicates that the combined transcriptional activation of TRAF-1, TRAF-2, IAP-1, and IAP-2 is required to suppress cell death by tumor necrosis factor (TNF). Here we show that NF-kappaB activation upregulates the caspase 8 inhibitor FLIP, resulting in increased resistance to Fas ligand (FasL) or TNF. Restoration of either the full-length 55-kDa long form of FLIP or an alternatively spliced short form of FLIP in NF-kappaB null cells inhibits TNF- and FasL-induced cell death efficiently, whereas the expression of IAP or TRAF family members only partially rescues cells from death. Resistance to either FasL- or TNF-induced apoptosis is overcome when cells are incubated in the presence of the protein synthesis inhibitor cycloheximide. This treatment leads to the rapid downregulation of FLIP but not to that of TRAF2. Our findings suggest that FLIP is an important mediator of NF-kappaB-controlled antiapoptotic signals.","TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders has long been attributed to induction of proinflammatory mediators. TNF also activates cell survival and death pathways, and recent studies demonstrated that TNF also causes inflammation by inducing cell death. The default response of most cells to TNF is survival and NF-κB-mediated upregulation of prosurvival molecules is a well-documented protective mechanism downstream of TNFR1. Recent studies revealed the existence of an NF-κB-independent cell death checkpoint that restricts cell demise by inactivating RIPK1. Disruption of this checkpoint leads to RIPK1 kinase-dependent death and causes inflammation in vivo. These revelations bring complexity to the control of TNF-induced cell death, and suggest clinical benefit of RIPK1 inhibitors in TNF-driven human inflammatory disorders.","Nuclear factor-kappaB (NF-kappaB) consists of a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, and survival. Inducible NF-kappaB activation depends on phosphorylation-induced proteosomal degradation of the inhibitor of NF-kappaB proteins (IkappaBs), which retain inactive NF-kappaB dimers in the cytosol in unstimulated cells. The majority of the diverse signaling pathways that lead to NF-kappaB activation converge on the IkappaB kinase (IKK) complex, which is responsible for IkappaB phosphorylation and is essential for signal transduction to NF-kappaB. Additional regulation of NF-kappaB activity is achieved through various post-translational modifications of the core components of the NF-kappaB signaling pathways. In addition to cytosolic modifications of IKK and IkappaB proteins, as well as other pathway-specific mediators, the transcription factors are themselves extensively modified. Tremendous progress has been made over the last two decades in unraveling the elaborate regulatory networks that control the NF-kappaB response. This has made the NF-kappaB pathway a paradigm for understanding general principles of signal transduction and gene regulation.","The ability of the vertebrate X-linked inhibitor of apoptosis (XIAP) protein to directly suppress apoptotic cell death pathways has been the subject of much research. Studies of this broadly expressed protein have largely focused on the unique interactions between XIAP and caspases - proteases that conduct and participate in the ordered disassembly of the cell during apoptosis. However, relatively less attention has been given to the RING domain of XIAP, which functions as an E3 ligase to catalyze the ubiquitination of substrate proteins. Here, we discuss the evidence implicating the RING domain of XIAP in the ubiquitin-mediated regulation of three, somewhat arbitrarily divided, categories of substrate: XIAP itself, XIAP-interacting proteins involved in apoptosis, and other targets whose physiological roles likely extend beyond cell death. Collectively, these multiple activities of XIAP show that this enigmatic protein participates in a range of cellular activities beyond apoptotic suppression.","The mixed lineage kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumour necrosis factor (TNF)-induced necroptosis. MLKL is phosphorylated by RIP3 and is recruited to the necrosome through its interaction with RIP3. However, it is still unknown how MLKL mediates TNF-induced necroptosis. Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. Furthermore, we identified that TRPM7 (transient receptor potential melastatin related 7) is a MLKL downstream target for the mediation of Ca(2+) influx and TNF-induced necroptosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced necroptosis.","Mixed lineage kinase domain-like (MLKL) is a component of the \"necrosome,\" the multiprotein complex that triggers tumor necrosis factor (TNF)-induced cell death by necroptosis. To define the specific role and molecular mechanism of MLKL action, we generated MLKL-deficient mice and solved the crystal structure of MLKL. Although MLKL-deficient mice were viable and displayed no hematopoietic anomalies or other obvious pathology, cells derived from these animals were resistant to TNF-induced necroptosis unless MLKL expression was restored. Structurally, MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation. Structure-guided mutation of the MLKL pseudoactive site resulted in constitutive, RIPK3-independent necroptosis, demonstrating that modification of MLKL is essential for propagation of the necroptosis pathway downstream of RIPK3.","Ubiquitination and deubiquitination are crucial for assembly and disassembly of signaling complexes. LUBAC-generated linear (M1) ubiquitin is important for signaling via various immune receptors. We show here that the deubiquitinases CYLD and A20, but not OTULIN, are recruited to the TNFR1- and NOD2-associated signaling complexes (TNF-RSC and NOD2-SC), at which they cooperate to limit gene activation. Whereas CYLD recruitment depends on its interaction with LUBAC, but not on LUBAC's M1-chain-forming capacity, A20 recruitment requires this activity. Intriguingly, CYLD and A20 exert opposing effects on M1 chain stability in the TNF-RSC and NOD2-SC. While CYLD cleaves M1 chains, and thereby sensitizes cells to TNF-induced death, A20 binding to them prevents their removal and, consequently, inhibits cell death. Thus, CYLD and A20 cooperatively restrict gene activation and regulate cell death via their respective activities on M1 chains. Hence, the interplay between LUBAC, M1-ubiquitin, CYLD, and A20 is central for physiological signaling through innate immune receptors.","Apoptosis is characterized by a series of dramatic perturbations to the cellular architecture that contribute not only to cell death, but also prepare cells for removal by phagocytes and prevent unwanted immune responses. Much of what happens during the demolition phase of apoptosis is orchestrated by members of the caspase family of cysteine proteases. These proteases target several hundred proteins for restricted proteolysis in a controlled manner that minimizes damage and disruption to neighbouring cells and avoids the release of immunostimulatory molecules.","Nuclear factor-κB (NF-κB) essential modulator (NEMO), a component of the inhibitor of κB kinase (IKK) complex, controls NF-κB signaling by binding to ubiquitin chains. Structural studies of NEMO provided a rationale for the specific binding between the UBAN (ubiquitin binding in ABIN and NEMO) domain of NEMO and linear (Met-1-linked) di-ubiquitin chains. Full-length NEMO can also interact with Lys-11-, Lys-48-, and Lys-63-linked ubiquitin chains of varying length in cells. Here, we show that purified full-length NEMO binds preferentially to linear ubiquitin chains in competition with lysine-linked ubiquitin chains of defined length, including long Lys-63-linked deca-ubiquitins. Linear di-ubiquitins were sufficient to activate both the IKK complex in vitro and to trigger maximal NF-κB activation in cells. In TNFα-stimulated cells, NEMO chimeras engineered to bind exclusively to Lys-63-linked ubiquitin chains mediated partial NF-κB activation compared with cells expressing NEMO that binds to linear ubiquitin chains. We propose that NEMO functions as a high affinity receptor for linear ubiquitin chains and a low affinity receptor for long lysine-linked ubiquitin chains. This phenomenon could explain quantitatively distinct NF-κB activation patterns in response to numerous cell stimuli.","The mitochondrial pathway of apoptosis proceeds when molecules sequestered between the outer and inner mitochondrial membranes are released to the cytosol by mitochondrial outer membrane permeabilization (MOMP). This process is controlled by the BCL-2 family, which is composed of both pro- and anti-apoptotic proteins. Although there is no disagreement that BCL-2 proteins regulate apoptosis, the mechanism leading to MOMP remains controversial. Current debate focuses on what interactions within the family are crucial to initiate MOMP. Specifically, do the BH3-only proteins directly engage BAX and/or BAK activation or do these proteins solely promote apoptosis by neutralization of anti-apoptotic BCL-2 proteins? We describe these models and contend that BH3-only proteins must perform both functions to efficiently engage MOMP and apoptosis.","The vertebrate transcription factor NF-kappaB is induced by over 150 different stimuli. Active NF-kappaB, in turn, participates in the control of transcription of over 150 target genes. Because a large variety of bacteria and viruses activate NF-kappaB and because the transcription factor regulates the expression of inflammatory cytokines, chemokines, immunoreceptors, and cell adhesion molecules, NF-kappaB has often been termed a 'central mediator of the human immune response'. This article contains a complete listing of all NF-kappaB inducers and target genes described to date. The collected data argue that NF-kappaB functions more generally as a central regulator of stress responses. In addition, NF-kappaB activation blocks apoptosis in several cell types. Coupling stress responsiveness and anti-apoptotic pathways through the use of a common transcription factor may result in increased cell survival following stress insults.","cFLIP (cellular FLICE-like inhibitory protein) is structurally related to caspase-8 but lacks proteolytic activity due to multiple amino acid substitutions of catalytically important residues. cFLIP protein is evolutionarily conserved and expressed as three functionally different isoforms in humans (cFLIPL, cFLIPS, and cFLIPR). cFLIP controls not only the classical death receptor-mediated extrinsic apoptosis pathway, but also the non-conventional pattern recognition receptor-dependent apoptotic pathway. In addition, cFLIP regulates the formation of the death receptor-independent apoptotic platform named the ripoptosome. Moreover, recent studies have revealed that cFLIP is also involved in a non-apoptotic cell death pathway known as programmed necrosis or necroptosis. These functions of cFLIP are strictly controlled in an isoform-, concentration- and tissue-specific manner, and the ubiquitin-proteasome system plays an important role in regulating the stability of cFLIP. In this review, we summarize the current scientific findings from biochemical analyses, cell biological studies, mathematical modeling, and gene-manipulated mice models to illustrate the critical role of cFLIP as a switch to determine the destiny of cells among survival, apoptosis, and necroptosis.","To identify proteins that bind mammalian IAP homolog A (MIHA, also known as XIAP), we used coimmuno-precipitation and 2D immobilized pH gradient/SDS PAGE, followed by electrospray ionization tandem mass spectrometry. DIABLO (direct IAP binding protein with low pI) is a novel protein that can bind MIHA and can also interact with MIHB and MIHC and the baculoviral IAP, OpIAP. The N-terminally processed, IAP-interacting form of DIABLO is concentrated in membrane fractions in healthy cells but released into the MIHA-containing cytosolic fractions upon UV irradiation. As transfection of cells with DIABLO was able to counter the protection afforded by MIHA against UV irradiation, DIABLO may promote apoptosis by binding to IAPs and preventing them from inhibiting caspases.","Key structural and catalytic features are conserved across the entire family of cysteine-dependent aspartate-specific proteases (caspases). Of the caspases involved in apoptosis signal transduction, the initiator caspases-2, -8 and -9 are activated at multi-protein activation platforms, and activation is thought to involve homo-dimerisation of the monomeric zymogens. Caspase-9, the essential initiator caspase required for apoptosis signalling through the mitochondrial pathway, is activated on the apoptosome complex, and failure to activate caspase-9 has profound pathophysiological consequences. Here, we review the pertinent literature on which the currently prevalent understanding of caspase-9 activation is based, extend this view by insight obtained from recent structural and kinetic studies on caspase-9 signalling, and describe an emerging model for the regulation of caspase-9 activation and activity that arise from the complexity of multi-protein interactions at the apoptosome. This integrated view allows us to postulate and to discuss functional consequences for caspase-9 activation and apoptosis execution that may take centre stage in future experimental cell research on apoptosis signalling.","Tumor Necrosis Factor alpha (TNFα, TNF) is a key mediator and regulator of mammalian immune responses in healthy organisms and in diseased conditions. TNF governs development of the immune system, cell survival signaling pathways, proliferation and regulates metabolic processes. Whereas TNF-induced NF-κB and MAP pro-survival kinase activities constitute its major biochemical functions, TNF can also stimulate cell death in certain pathological situations. TNF-induced signal transduction pathways are tightly regulated through ubiquitination and phosphorylation of molecules partaking in all TNF-dependent membrane-associated and intracellular protein signaling complexes. Deregulated TNF signaling in individuals carrying naturally occurring genetic mutations in proteins that mediate TNF signaling, or in corresponding genetically modified animal models, results in severe pathologies. In this review we will describe the current knowledge of TNF signaling and its relevance for human health.","The NK-kappa B transcription factor complex is sequestered in the cytoplasm by the inhibitory protein I kappa B-alpha (MAD-3). Various cellular stimuli relieve this inhibition by mechanisms largely unknown, leading to NF-kappa B nuclear localization and transactivation of its target genes. It is demonstrated here with human T lymphocytes and monocytes that different stimuli, including tumor necrosis factor alpha and phorbol 12-myristate 13-acetate, cause rapid degradation of I kappa B-alpha, with concomitant activation of NF-kappa B, followed by a dramatic increase in I kappa B-alpha mRNA and protein synthesis. Transfection studies reveal that the I kappa B-alpha mRNA and the encoded protein are potently induced by NF-kappa B and by homodimers of p65 and of c-Rel. We propose a model in which NF-kappa B and I kappa B-alpha mutually regulate each other in a cycle: saturating amounts of the inhibitory I kappa B-alpha protein are destroyed upon stimulation, allowing rapid activation of NF-kappa B. Subsequently, I kappa B-alpha mRNA and protein levels are quickly induced by the activated NF-kappa B. This resurgence of I kappa B-alpha protein acts to restore an equilibrium in which NF-kappa B is again inhibited.","The kinase RIPK1 is an essential signaling node in various innate immune signaling pathways being most extensively studied in the TNFR1 signaling pathway. TNF signaling can result in different biological outcomes including gene activation and cell death induction in the form of apoptosis or necroptosis. RIPK1 is believed to be crucial for regulating the balance between these opposing outcomes. It is therefore not surprising that RIPK1 is highly regulated, most notably by phosphorylation, ubiquitination, and their respective reversals. In this review, we discuss the biological functions of RIPK1 within the context of TNFR1 signaling. Finally, we discuss recent advances in the knowledge on three ubiquitin E3 ligases that exert regulatory functions on RIPK1 signaling: cIAP1, cIAP2, and LUBAC."],"pubmed_title":["An unexpected twist to the activation of IKKβ: TAK1 primes IKKβ for activation by autophosphorylation.","FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP.","cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms.","IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer.","LUBAC-Recruited CYLD and A20 Regulate Gene Activation and Cell Death by Exerting Opposing Effects on Linear Ubiquitin in Signaling Complexes.","Analysis of nuclear factor-κB (NF-κB) essential modulator (NEMO) binding to linear and lysine-linked ubiquitin chains and its role in the activation of NF-κB.","How do BCL-2 proteins induce mitochondrial outer membrane permeabilization?","Intracellular regulation of TNF activity in health and disease.","The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination.","Regulated necrosis: the expanding network of non-apoptotic cell death pathways.","The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism.","Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha.","Bcl-2 proteins and apoptosis: choose your partner.","Holding RIPK1 on the Ubiquitin Leash in TNFR1 Signaling.","Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis.","Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3.","Mechanisms of apoptosis.","The central role of initiator caspase-9 in apoptosis signal transduction and the regulation of its activation and activity on the apoptosome.","XIAP as a ubiquitin ligase in cellular signaling.","Apoptosis: controlled demolition at the cellular level.","Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3.","Activators and target genes of Rel/NF-kappaB transcription factors.","Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis.","The 'complexities' of life and death: death receptor signalling platforms.","Survival function of the FADD-CASPASE-8-cFLIP(L) complex.","Role of Bcl-2 family proteins and caspases in the regulation of apoptosis.","Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.","Mathematical modeling of the molecular switch of TNFR1-mediated signaling pathways applying Petri net formalism and in silico knockout analysis.","The NF-kappaB family of transcription factors and its regulation.","More to Life than NF-κB in TNFR1 Signaling.","Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction.","NF-kappaB signals induce the expression of c-FLIP.","Regulation of apoptosis by XIAP ubiquitin-ligase activity."],"pubmed_authors":["Dillon Christopher P CP, Oberst Andrew A, Weinlich Ricardo R, Janke Laura J LJ, Kang Tae-Bong TB, Ben-Moshe Tehila T, Mak Tak W TW, Wallach David D, Green Douglas R DR","Wang Huayi H, Sun Liming L, Su Lijing L, Rizo Josep J, Liu Lei L, Wang Li-Feng LF, Wang Fu-Sheng FS, Wang Xiaodong X","Gyrd-Hansen Mads M, Meier Pascal P","Ting Adrian T AT, Bertrand Mathieu J M MJM","Varfolomeev Eugene E, Vucic Domagoj D","Oberst Andrew A, Dillon Christopher P CP, Weinlich Ricardo R, McCormick Laura L LL, Fitzgerald Patrick P, Pop Cristina C, Hakem Razq R, Salvesen Guy S GS, Green Douglas R DR","Würstle Maximilian L ML, Laussmann Maike A MA, Rehm Markus M","Ola Mohammad Shamsul MS, Nawaz Mohd M, Ahsan Haseeb H","Zhang Jiazhen J, Clark Kristopher K, Lawrence Toby T, Peggie Mark W MW, Cohen Philip P","Kensche Tobias T, Tokunaga Fuminori F, Ikeda Fumiyo F, Goto Eiji E, Iwai Kazuhiro K, Dikic Ivan I","Tsuchiya Yuichi Y, Nakabayashi Osamu O, Nakano Hiroyasu H","Feoktistova Maria M, Geserick Peter P, Kellert Beate B, Dimitrova Diana Panayotova DP, Langlais Claudia C, Hupe Mike M, Cain Kelvin K, MacFarlane Marion M, Häcker Georg G, Leverkus Martin M","Brown K K, Park S S, Kanno T T, Franzoso G G, Siebenlist U U","Murphy James M JM, Czabotar Peter E PE, Hildebrand Joanne M JM, Lucet Isabelle S IS, Zhang Jian-Guo JG, Alvarez-Diaz Silvia S, Lewis Rowena R, Lalaoui Najoua N, Metcalf Donald D, Webb Andrew I AI, Young Samuel N SN, Varghese Leila N LN, Tannahill Gillian M GM, Hatchell Esme C EC, Majewski Ian J IJ, Okamoto Toru T, Dobson Renwick C J RC, Hilton Douglas J DJ, Babon Jeffrey J JJ, Nicola Nicos A NA, Strasser Andreas A, Silke John J, Alexander Warren S WS","Draber Peter P, Kupka Sebastian S, Reichert Matthias M, Draberova Helena H, Lafont Elodie E, de Miguel Diego D, Spilgies Lisanne L, Surinova Silvia S, Taraborrelli Lucia L, Hartwig Torsten T, Rieser Eva E, Martino Luigi L, Rittinger Katrin K, Walczak Henning H","Chipuk Jerry E JE, Green Douglas R DR","Reed J C JC","Taylor Rebecca C RC, Cullen Sean P SP, Martin Seamus J SJ","Galbán S S, Duckett C S CS","Schile Andrew J AJ, García-Fernández María M, Steller Hermann H","Shore Gordon C GC, Nguyen Mai M","Dickens Laura S LS, Powley Ian R IR, Hughes Michelle A MA, MacFarlane Marion M","Sun Xiaoqing X, Yin Jianping J, Starovasnik Melissa A MA, Fairbrother Wayne J WJ, Dixit Vishva M VM","Vanden Berghe Tom T, Linkermann Andreas A, Jouan-Lanhouet Sandrine S, Walczak Henning H, Vandenabeele Peter P","Micheau O O, Lens S S, Gaide O O, Alevizopoulos K K, Tschopp J J","Amstein Leonie K LK, Ackermann Jörg J, Hannig Jennifer J, Đikić Ivan I, Fulda Simone S, Koch Ina I","Haas Tobias L TL, Emmerich Christoph H CH, Gerlach Björn B, Schmukle Anna C AC, Cordier Stefanie M SM, Rieser Eva E, Feltham Rebecca R, Vince James J, Warnken Uwe U, Wenger Till T, Koschny Ronald R, Komander David D, Silke John J, Walczak Henning H","Verhagen A M AM, Ekert P G PG, Pakusch M M, Silke J J, Connolly L M LM, Reid G E GE, Moritz R L RL, Simpson R J RJ, Vaux D L DL","Kovalenko Andrew A, Chable-Bessia Christine C, Cantarella Giuseppina G, Israël Alain A, Wallach David D, Courtois Gilles G","Pahl H L HL","Cai Zhenyu Z, Jitkaew Siriporn S, Zhao Jie J, Chiang Hsueh-Cheng HC, Choksi Swati S, Liu Jie J, Ward Yvona Y, Wu Ling-Gang LG, Liu Zheng-Gang ZG","Peltzer Nieves N, Darding Maurice M, Walczak Henning H","Oeckinghaus Andrea A, Ghosh Sankar S"],"additional_accession":[]},"is_claimable":false,"name":"Amstein2022 - TNFR1 Signal Transduction, Petri Net","description":"No 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