RIP Kinase-Dependent Necrosis Drives Lethal Systemic Inflammatory Response Syndrome

Duprez, Linde; Takahashi, Nozomi; Hauwermeiren, Filip Van; Vandendriessche, Benjamin; Goossens, Vera; Berghe, Tom Vanden; Declercq, Wim; Libert, Claude; Cauwels, Anje; Vandenabeele, Peter

doi:10.1016/j.immuni.2011.09.020

Cited by 510 publications

(539 citation statements)

References 64 publications

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“…29 Furthermore, a subline of L929 has been described that does not require caspase inhibition for this response. 14 Figure 2b shows that the L929 subline used in our laboratory falls into this latter category, given that treatment with the pan-caspase inhibitor Q-VD-OPh (QVD) 30 failed to prevent death induced by TNF in L929, even though the same concentrations of QVD were able Figure 1 Expression and dimerization of RIPK1 gyrase and RIPK3 gyrase is sufficient to cause death of MEFs. (a) FLAG-tagged RIPK1 gyrase B and FLAGtagged RIPK3 gyrase B constructs.…”

Section: Resultsmentioning

confidence: 99%

RIPK1- and RIPK3-induced cell death mode is determined by target availability

et al. 2014

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Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential for MLKL-dependent but not for caspase 8-dependent death. When RIPK1 or RIPK3 proteins were dimerized, the mode of cell death was determined by the availability of downstream molecules such as FADD, caspase 8 and MLKL. These observations imply that rather than a 'switch' operating between the two modes of cell death, the final mechanism depends on levels of the respective signaling and effector proteins. Mammalian cells can use a number of mechanisms to kill themselves. The best characterized depends on the Bcl-2 family members Bax and Bak that work via mitochondria to activate caspases. 1 Some caspases, notably caspase 8, can be activated independently of Bcl-2 family members, for example, after stimulation of members of the TNF receptor superfamily. 2 Recently, it has become apparent that some of these receptors, including TNFR1, can activate a third suicide mechanism that does not require caspases, and in which the morphology of the dying cell differs from classical apoptosis. This form of cell death, termed 'necroptosis', can often be blocked by necrostatin-1 (nec-1), an inhibitor of the kinase activity of receptor-interacting protein kinase 1 (RIPK1). 3,4 Accordingly, observations from several groups have shown that in some cell types, expression of RIPK1 can signal cell death by caspase-independent necroptosis. 5 It has previously been revealed that RIPK1 could function downstream of death receptors, but in those cases, cell death was usually blocked by coexpression of the viral inhibitor of caspases 1 and 8, CrmA, 6 and typically exhibited a classical 'apoptotic' morphology. It was revealed that RIPK1 engages FADD via homotypic binding of their death domains (DDs), and FADD in turn activates caspase 8. 6,7 RIPK3, like RIPK1, bears a kinase domain and RIP homology interaction motif (RHIM), but unlike RIPK1 does not have a DD. 8-11 RIPK3 is required for necroptosis. 12,13 Furthermore, RIPK1 appears to activate RIPK3 in this pathway, as cell death could be blocked by nec-1. 14 RIPK3 activates, by phosphorylation, MLKL, a pseudokinase essential for this death pathway. [15][16][17] Once activated, MLKL forms multimers that trigger breaches of the plasma membrane. [18][19][20] Although RIPK3 is necessary for necroptosis, it is unclear whether activation of RIPK3 is sufficient for cell death, because TNF activates signaling ...

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Section: Resultsmentioning

confidence: 99%

RIPK1- and RIPK3-induced cell death mode is determined by target availability

et al. 2014

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“…TAK1 may also be potentially hyperactivated when caspase is exogenously inhibited by viral infection or under yet unidentified conditions, which could be associated with pathologic necroptotic conditions such as ischemic tissue injuries and systemic inflammation. 90,91 Functional Interaction of TAK1 and Other Cell Death Molecules In Vivo…”

Section: Pathology Of Tak1 Deficiency In a Variety Of Tissue In Mousementioning

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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“…In support of this notion is the finding that deletion of the RIP kinase 3 (RIPK3) gene, a master regulator of programmed cell death by necroptosis 99 , is sufficient per se to confer tissue damage control and disease tolerance to systemic polymicrobial infection in mice 100 . Moreover, deletion of the Birc3 (cIAP2) gene, encoding a E3 ubiquitin ligase that suppresses necroptosis, impairs tissue damage control and disease tolerance to influenza virus infection in mice 101 .…”

Section: Boxmentioning

confidence: 99%

Tissue damage control in disease tolerance

Soares

Gozzelino

Weis

2014

Trends in Immunology

159

174

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The deposited article is a prost-print version.This publication hasn't any creative commons license associated.This deposit is composed by the main article, and it hasn't any supplementary materials associated.Immune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.Fundação para a Ciência e Tecnologia grants: (PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, SFRH/BPD/44256/2008); European Commission 7th Framework grant: (ERC-2011-AdG. 294709-DAMAGECONTROL); Deutsche Forschungsgemeinschaft grant: (DFG WE 4971/3-1).info:eu-repo/semantics/publishedVersio

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RIP Kinase-Dependent Necrosis Drives Lethal Systemic Inflammatory Response Syndrome

Cited by 510 publications

References 64 publications

RIPK1- and RIPK3-induced cell death mode is determined by target availability

RIPK1- and RIPK3-induced cell death mode is determined by target availability

TAK1 control of cell death

Tissue damage control in disease tolerance

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