Tumor necrosis factor (TNF) is crucial for innate immunity, but deregulated TNF signaling also plays an eminent role in the pathogenesis of many chronic inflammatory diseases and cancer‐related ...inflammation. The signals that mediate both the beneficial and the harmful effects of TNF are initiated when TNF binds to its receptors on the surface of target cells. TNF receptor 1 (TNFR1) is ubiquitously expressed, whereas TNFR2 is mainly expressed on lymphocytes and endothelial cells. This review focuses on the molecular and physiological consequences of the interaction of TNF with TNFR1. The different outcomes of TNF signaling originate at the apical signaling complex that forms when TNF binds to TNFR1, the TNFR1 signaling complex (TNF‐RSC). By integrating recently gained insight on the functional importance of the presence of different types of ubiquitination in the TNF‐RSC, including linear ubiquitin linkages generated by the linear ubiquitin chain assembly complex (LUBAC), with the equally recent elucidation of the mode in which ubiquitin‐binding domains interact with specific di‐ubiquitin linkages, this review develops a new concept for the way the concerted action of different ubiquitination events enables the TNF‐RSC to generate its signaling output in a spatio‐temporally controlled manner. Finally, it will be explained how these new findings and the emerging concept of differential ubiquitination governing the TNF‐RSC may impact future research on the molecular mechanism of TNF signaling and the function of this cytokine in normal physiology, chronic inflammation, and cancer.
The immune system has developed multiple ways to fight infection. Yet, it is constantly tasked with overcoming newly developing pathogenic mechanisms of resistance to host immunity. In most mammals, ...the stimulation of both innate and adaptive immune receptors can result in gene activation and cell death induction by apoptosis and necroptosis. RIPK1 and RIPK3 are key mediators of necroptosis; however, new findings support their role in the regulation of cell death-independent proinflammatory signaling. We discuss here the biological functions of RIPK1 and RIPK3, how they regulate cell death and inflammation, and the interplay between them. Finally, we discuss recent advances in our knowledge of linear ubiquitination which, alongside RIPK3 and caspase-8, exerts regulatory functions on RIPK1-mediated inflammation. Together, this review examines the complex interplay between RIPK1, RIPK3, and LUBAC that is important in regulating cell death and inflammatory signaling.
RIPK3 induces necroptosis by RHIM-containing proteins.
The RIPK3 kinase domain also bears scaffolding functions.
RIPK1 and RIPK3, but not MLKL, can also regulate proinflammatory signaling independently of their role in cell death.
RIPK1 and RIPK3 are crucial to fighting infection by both cell death-dependent and −independent functions.
RIPK3, caspase-8, and LUBAC prevent RIPK1-mediated proinflammatory cytokine production.
Mitochondria play a central role in maintaining cells alive, but are also important mediators of cell death. The main event in mitochondrial signalling and control of apoptosis is the ...permeabilisation of the outer mitochondrial membrane and the release of pro-apoptotic proteins into the cytosol from the mitochondrial intermembrane space. With respect to death receptor-mediated apoptosis, the activation of the mitochondrial pathway is required for apoptosis induction in cells which are described as “type II” cells whereas “type I” cells do not require it. In type I cells, activation of the extrinsic pathway is sufficient to induce apoptosis. This review deals with the events that enable cell death in type II cells, i.e., the signals that lead from death receptor stimulation to permeabilisation of the outer mitochondrial membrane. Caspase-8 and Bid are the known procurers of the death signal in this part of the apoptotic pathway. Currently many exciting new findings are emerging concerning the regulation of caspase-8 and Bid function and activation. We will take you on a journey through these new developments and point out what we consider the major unknowns in this field. We end our review on an up-to-date discussion of the determinants of the type I–type II cell distinction. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.
► We describe the role of mitochondria in caspase-8 signalling. ► Polyubiquitination of caspase-8 at the DISC modulates its activation. ► The cardiolipin enriched “mitosome” is a new activation platform for caspase-8. ► MTCH2/MIMP facilitates the recruitment of active tBid to the mitochondria. ► The type I/type II cell discrimination is also due to differences on XIAP levels.
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.
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.
Linear ubiquitination at a glance Spit, Maureen; Rieser, Eva; Walczak, Henning
Journal of cell science,
01/2019, Letnik:
132, Številka:
2
Journal Article
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Ubiquitination (also known as ubiquitylation) is a post-translational modification that creates versatility in cell signalling and regulates a multitude of cellular processes. Its versatility lies in ...the capacity to form eight different inter-ubiquitin linkages through the seven lysine residues of ubiquitin and through its N-terminal methionine (M1). The latter, referred to as linear or M1 linkage, is created by the linear ubiquitin chain assembly complex (LUBAC), the only E3 ligase known to date that is capable of forming linear ubiquitin chains
Linear ubiquitin chains are crucial modulators of innate and adaptive immune responses, and act by regulating inflammatory and cell death signalling. In this Cell Science at a Glance article and the accompanying poster, we review the current knowledge on the role of LUBAC and linear ubiquitination in immune signalling and human physiology. We specifically focus on the role for LUBAC in signalling that is induced by the cytokine tumour necrosis factor (TNF) and its role in inflammation, gene activation and cell death. Furthermore, we highlight the roles of deubiquitinases (DUBs) that cleave M1 linkages and add an additional layer in the control of LUBAC-mediated immune signalling.
Linear ubiquitination in immunity Shimizu, Yutaka; Taraborrelli, Lucia; Walczak, Henning
Immunological reviews,
July 2015, Letnik:
266, Številka:
1
Journal Article
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Summary
Linear ubiquitination is a post‐translational protein modification recently discovered to be crucial for innate and adaptive immune signaling. The function of linear ubiquitin chains is ...regulated at multiple levels: generation, recognition, and removal. These chains are generated by the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin E3 capable of forming the linear ubiquitin linkage de novo. LUBAC is not only relevant for activation of nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinases (MAPKs) in various signaling pathways, but importantly, it also regulates cell death downstream of immune receptors capable of inducing this response. Recognition of the linear ubiquitin linkage is specifically mediated by certain ubiquitin receptors, which is crucial for translation into the intended signaling outputs. LUBAC deficiency results in attenuated gene activation and increased cell death, causing pathologic conditions in both, mice, and humans. Removal of ubiquitin chains is mediated by deubiquitinases (DUBs). Two of them, OTULIN and CYLD, are constitutively associated with LUBAC. Here, we review the current knowledge on linear ubiquitination in immune signaling pathways and the biochemical mechanisms as to how linear polyubiquitin exerts its functions distinctly from those of other ubiquitin linkage types.
The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of ...the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSCs, we found a striking parallel, whereby only those with high cytotoxic activity against MSCs responded to MSC infusion, whereas those with low activity did not. The need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSCs and produce indoleamine 2,3-dioxygenase, which is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSCs or that all patients could be treated with ex vivo apoptotic MSCs.
The members of the tumour necrosis factor (TNF) superfamily of cytokines play important roles in the regulation of various immune-cell functions. Likewise, induction of cell death by apoptosis is ...indispensable for the normal functioning of the immune system. There are two major pathways of apoptosis induction. The intrinsic, or mitochondrial, pathway is regulated by the activation and interaction of members of the Bcl-2 family. The extrinsic, or death receptor, pathway is triggered by certain TNF family members when they engage their respective cognate receptors on the surface of the target cell. Hence, cell-to-cell-mediated death signals are induced by activation of these death receptor-ligand systems. Besides TNF itself and the CD95 (Fas/APO-1) ligand (FasL/Apo1L), the TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) belongs to the subfamily of ligands that is responsible for extrinsic induction of cell death. Depending on their status of stimulation, TRAIL can be expressed by various cells of the immune system, amongst them natural killer (NK) cells, T cells, natural killer T cells (NKT cells), dendritic cells and macrophages. TRAIL has been implicated in immunosuppressive, immunoregulatory and immune-effector functions. With respect to pathological challenges, TRAIL and its receptors have been shown to play important roles in the immune response to viral infections and in immune surveillance of tumours and metastases. In this review we summarize the current knowledge on the role of TRAIL and its receptors in the immune system and, based on this, we discuss future directions of research into the diverse functions of this fascinating receptor-ligand system.
Poly-ubiquitination in TNFR1-mediated necroptosis Dondelinger, Yves; Darding, Maurice; Bertrand, Mathieu J. M. ...
Cellular and molecular life sciences : CMLS,
06/2016, Letnik:
73, Številka:
11-12
Journal Article
Recenzirano
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Tumor necrosis factor (TNF) is a master pro-inflammatory cytokine, and inappropriate TNF signaling is implicated in the pathology of many inflammatory diseases. Ligation of TNF to its receptor TNFR1 ...induces the transient formation of a primary membrane-bound signaling complex, known as complex I, that drives expression of pro-survival genes. Defective complex I activation results in induction of cell death, in the form of apoptosis or necroptosis. This switch occurs via internalization of complex I components and assembly and activation of secondary cytoplasmic death complexes, respectively known as complex II and necrosome. In this review, we discuss the crucial regulatory functions of ubiquitination—a post-translational protein modification consisting of the covalent attachment of ubiquitin, and multiples thereof, to target proteins—to the various steps of TNFR1 signaling leading to necroptosis.
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