The Role of the Kinases RIP1 and RIP3 in TNF-Induced Necrosis

Vandenabeele, Peter; Declercq, Wim; Herreweghe, Franky Van; Berghe, Tom Vanden

doi:10.1126/scisignal.3115re4

Cited by 420 publications

(395 citation statements)

References 100 publications

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“…RIP1 contains a kinase domain, an RHIM domain, and a death domain (DD) (Figure 1a). 48 As dimerization or polymerization of RIP1 is considered to be involved in TNF-induced necroptosis and/or apoptosis, 49 we first evaluated the contributions of these domains to the interaction between RIP1 proteins. HA-RIP1 mutants ( Figure 1a) were coexpressed with or without Flag-tagged full-length RIP1 in 293T cells and their interaction was determined by coimmunoprecipitation (Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

“…Meanwhile, the analysis of RHIM revealed bright fluorescent spots (Figure 1d) and unresolved bleaching steps (Figure 1g), suggesting RIP1's RHIM domain potentially contributes to polymerization, as is consistent with a recent report indicating RHIM forms amyloidal complex. 47 As RIP1 is involved in necroptosis and apoptosis, 48 we checked the requirement of its RHIM and DD in cell death. According to previous reports, pan-caspase inhibitor Z-ValAla-DL-Asp-fluoromethylketone (zVAD) was used to distinguish apoptosis from necroptosis.…”

Section: Resultsmentioning

confidence: 99%

“…RIP1 contains a kinase domain, an RHIM domain, and a death domain (DD) (Figure 1a). 48 As dimerization or polymerization …”

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confidence: 99%

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Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

et al. 2014

Cell Death Differ

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Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL). It is known that RIP1 and RIP3 form heterodimeric filamentous scaffold in necrosomes through their RIP homotypic interaction motif (RHIM) domain-mediated oligomerization, but the signaling events based on this scaffold has not been fully addressed. By using inducible dimer systems we found that RIP1-RIP1 interaction is dispensable for necroptosis; RIP1-RIP3 interaction is required for necroptosis signaling, but there is no necroptosis if no additional RIP3 protein is recruited to the RIP1-RIP3 heterodimer, and the interaction with RIP1 promotes the RIP3 to recruit other RIP3; RIP3-RIP3 interaction is required for necroptosis and RIP3-RIP3 dimerization is sufficient to induce necroptosis; and RIP3 dimer-induced necroptosis requires MLKL. We further show that RIP3 oligomer is not more potent than RIP3 dimer in triggering necroptosis, suggesting that RIP3 homo-interaction in the complex, rather than whether RIP3 has formed homo polymer, is important for necroptosis. RIP3 dimerization leads to RIP3 intramolecule autophosphorylation, which is required for the recruitment of MLKL. Interestingly, phosphorylation of one of RIP3 in the dimer is sufficient to induce necroptosis. As RIP1-RIP3 heterodimer itself cannot induce necroptosis, the RIP1-RIP3 heterodimeric amyloid fibril is unlikely to directly propagate necroptosis. We propose that the signaling events after the RIP1-RIP3 amyloid complex assembly are the recruitment of free RIP3 by the RIP3 in the amyloid scaffold followed by autophosphorylation of RIP3 and subsequent recruitment of MLKL by RIP3 to execute necroptosis. Cell Death and Differentiation (2014) 21, 1709-1720; doi:10.1038/cdd.2014.77; published online 6 June 2014Necroptosis is a type of programmed necrosis characterized by necrotic morphological changes, including cellular organelle swelling, cell membrane rupture, 1-3 and dependence of receptor-interacting protein (RIP)1 4 and RIP3. [5][6][7] Physiological function of necroptosis has been illustrated in host defense, [8][9][10][11] inflammation, 12-16 tissue injury, 10,17,18 and development. [19][20][21] Necroptosis can be induced by a number of different extracellular stimuli such as tumor necrosis factor (TNF). TNF stimulation leads to formation of TNF receptor 1 (TNFR1) signaling complex (named complex I), and complex II containing RIP1, TRADD, FAS-associated protein with a death domain (FADD), and caspase-8, of which the activation initiates apoptosis. If cells have high level of RIP3, RIP1 recruits RIP3 to form necrosome containing FADD, [22][23][24] caspase-8, RIP1, and RIP3, and the cells undergo necroptosis. 25,26 Caspase-8 and FADD negatively regulates necroptosis, 27-30 because RIP1, RIP3, and CYLD are potential substrates of caspase-8. [31][32][33][34] Necrosome also suppresses apoptosis but the underlying mechanism has not been described yet. Mixed-lineage kinase domain-like (ML...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

et al. 2014

Cell Death Differ

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“…43 Caspase-8 activation initiates a caspase cascade, which leads to apoptotic cell death. 44 If caspase-8 is inhibited, Complex IIb which include FADD, RIPK1 and RIPK3 is formed. 45 RIPK1-RIPK3 executes necroptosis through downstream molecule such as MLKL [46][47][48] TAK1 control of cell death SR Mihaly et al receptors, and activates cellular processes to mitigate stress conditions through intracellular signaling pathways including, but not limited to, IKK-NF-kB and MAPK pathways ( Figure 1).…”

Section: Tak1 Activation and Downstream Pathwaysmentioning

confidence: 99%

TAK1 control of cell death

2014

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Programmed cell death, a physiologic process for removing cells, is critically important in normal development and for elimination of damaged cells. Conversely, unattended cell death contributes to a variety of human disease pathogenesis. Thus, precise understanding of molecular mechanisms underlying control of cell death is important and relevant to public health. Recent studies emphasize that transforming growth factor-b-activated kinase 1 (TAK1) is a central regulator of cell death and is activated through a diverse set of intra-and extracellular stimuli. The physiologic importance of TAK1 and TAK1-binding proteins in cell survival and death has been demonstrated using a number of genetically engineered mice. These studies uncover an indispensable role of TAK1 and its binding proteins for maintenance of cell viability and tissue homeostasis in a variety of organs. TAK1 is known to control cell viability and inflammation through activating downstream effectors such as NF-jB and mitogen-activated protein kinases (MAPKs). It is also emerging that TAK1 regulates cell survival not solely through NF-jB but also through NF-jB-independent pathways such as oxidative stress and receptor-interacting protein kinase 1 (RIPK1) kinase activity-dependent pathway. Moreover, recent studies have identified TAK1's seemingly paradoxical role to induce programmed necrosis, also referred to as necroptosis. This review summarizes the consequences of TAK1 deficiency in different cell and tissue types from the perspective of cell death and also focuses on the mechanism by which TAK1 complex inhibits or promotes programmed cell death. This review serves to synthesize our current understanding of TAK1 in cell survival and death to identify promising directions for future research and TAK1's potential relevance to human disease pathogenesis.

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“…83 Understanding the immunogenicity of necrotic cell death is becoming important because it frequently induces robust inflammatory reactions to mount protective immune responses (Table 1). 84,85,86 Although necrosis has long been viewed as non-PCD, its execution was shown to be controlled by specific signal-transduction pathways and catabolic mechanism. 87,88,89 This alternative form of necrotic PCD, aptly termed necroptosis (type 3 PCD), is induced by tumor necrosis factor (TNF) receptor signaling that involves activation of the receptor-interacting protein (RIP) family.…”

Section: Necrotic Cell Death and Necroptosismentioning

confidence: 99%

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

2013

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Apoptotic cell death generally characterized by a morphologically homogenous entity has been considered to be essentially non-immunogenic. However, apoptotic cancer cell death, also known as type 1 programmed cell death (PCD), was recently found to be immunogenic after treatment with several chemotherapeutic agents and oncolytic viruses through the emission of various danger-associated molecular patterns (DAMPs). Extensive studies have revealed that two different types of immunogenic cell death (ICD) inducers, recently classified by their distinct actions in endoplasmic reticulum (ER) stress, can reinitiate immune responses suppressed by the tumor microenvironment. Indeed, recent clinical studies have shown that several immunotherapeutic modalities including therapeutic cancer vaccines and oncolytic viruses, but not conventional chemotherapies, culminate in beneficial outcomes, probably because of their different mechanisms of ICD induction. Furthermore, interests in PCD of cancer cells have shifted from its classical form to novel forms involving autophagic cell death (ACD), programmed necrotic cell death (necroptosis), and pyroptosis, some of which entail immunogenicity after anticancer treatments. In this review, we provide a brief outline of the well-characterized DAMPs such as calreticulin (CRT) exposure, high-mobility group protein B1 (HMGB1), and adenosine triphosphate (ATP) release, which are induced by the morphologically distinct types of cell death. In the latter part, our review focuses on how emerging oncolytic viruses induce different forms of cell death and the combinations of oncolytic virotherapies with further immunomodulation by cyclophosphamide and other immunotherapeutic modalities foster dendritic cell (DC)-mediated induction of antitumor immunity. Accordingly, it is increasingly important to fully understand how and which ICD inducers cause multimodal ICD, which should aid the design of reasonably multifaceted anticancer modalities to maximize ICD-triggered antitumor immunity and eliminate residual or metastasized tumors while sparing autoimmune diseases.

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The Role of the Kinases RIP1 and RIP3 in TNF-Induced Necrosis

Cited by 420 publications

References 100 publications

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

TAK1 control of cell death

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

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