RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis

Takahashi, Nozomi; Vereecke, Lars; Bertrand, Mathieu J.M.; Duprez, Linde; Berger, Scott B.; Divert, Tatyana; Gonçalves, Amanda; Sze, Mozes; Gilbert, Barbara; Kourula, Stephanie; Goossens, Vera; Lefebvre, Sylvie; Günther, Claudia; Becker, Christoph; Bertin, John; Gough, Peter J.; Declercq, Wim; Loo, Geert; Vandenabeele, Peter

doi:10.1038/nature13706

Cited by 289 publications

(279 citation statements)

References 42 publications

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“…Although access to detailed histopathological analysis was not available to us in this study, it is notable that the DKO phenotype bears similarity to that reported recently for selective RIPK1 KO in intestinal epithelial cells. [50][51][52] The latter involves kinaseindependent RIPK1 activity, which confers stabilization of several pro-survival proteins, including TRAF2, cIAPs and cFLIP. 52 It will be interesting to investigate whether TRAF2 is linked to the kinase-independent functions of RIPK1 and/or RIPK3.…”

Section: Discussionmentioning

confidence: 99%

TRAF2 is a biologically important necroptosis suppressor

et al. 2015

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Tumor necrosis factor α (TNFα) triggers necroptotic cell death through an intracellular signaling complex containing receptorinteracting protein kinase (RIPK) 1 and RIPK3, called the necrosome. RIPK1 phosphorylates RIPK3, which phosphorylates the pseudokinase mixed lineage kinase-domain-like (MLKL)-driving its oligomerization and membrane-disrupting necroptotic activity. Here, we show that TNF receptor-associated factor 2 (TRAF2)-previously implicated in apoptosis suppression-also inhibits necroptotic signaling by TNFα. TRAF2 disruption in mouse fibroblasts augmented TNFα-driven necrosome formation and RIPK3-MLKL association, promoting necroptosis. TRAF2 constitutively associated with MLKL, whereas TNFα reversed this via cylindromatosis-dependent TRAF2 deubiquitination. Ectopic interaction of TRAF2 and MLKL required the C-terminal portion but not the N-terminal, RING, or CIM region of TRAF2. Induced TRAF2 knockout (KO) in adult mice caused rapid lethality, in conjunction with increased hepatic necrosome assembly. By contrast, TRAF2 KO on a RIPK3 KO background caused delayed mortality, in concert with elevated intestinal caspase-8 protein and activity. Combined injection of TNFR1-Fc, Fas-Fc and DR5-Fc decoys prevented death upon TRAF2 KO. However, Fas-Fc and DR5-Fc were ineffective, whereas TNFR1-Fc and interferon α receptor (IFNAR1)-Fc were partially protective against lethality upon combined TRAF2 and RIPK3 KO. These results identify TRAF2 as an important biological suppressor of necroptosis in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

TRAF2 is a biologically important necroptosis suppressor

et al. 2015

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“…RIP1 functions to protect cells from excessive caspase-8-mediated apoptosis and TNF-driven inflammation to maintain cell homeostasis in barrier tissues such as the gut epithelium and skin. 28,29 Pyroptosis. Cell death by pyroptosis was first observed in macrophages following infection with Shigella flexneri or Salmonella typhimurium.…”

Section: Caspases In Non-apoptotic Cell Deathmentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

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Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

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“…40 Recently, in a mouse model of inflammation in the skin that is induced by SHARPIN-deficiency, RIPK1 kinase-dead mice displayed significant rescue, 20 whereas in the models of gut inflammation the kinase activity of RIPK1 did not promote severe colitis. 24,41 Further, it was shown that RIPK1 and RIPK3 are found in a complex with caspase 8 and caspase 1 where the kinase activity of RIPK1 is dispensable. 42,43 However, in vivo deficiency of RIPK1 kinase activity is shown to be deleterious for the host after Vaccinia virus infection.…”

Section: Ripk1 Interacts With Various Proteins Such As Ciaps Andmentioning

confidence: 99%

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

et al. 2016

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Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1K45A mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1K45A macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli. Apoptosis is considered as the predominant, programmed pathway of cell death; however, recently several pathways of regulated cell death have been shown to operate in cells that are considered highly inflammatory.1,2 Although apoptosis has a major role during fetal development, 3 regulated necrotic cell death does not appear to influence fetal development. 4 Interestingly, receptor interacting protein kinase 1 (RIPK1) deficiency cause embryonic lethality, suggesting a key role of RIPK1 in host survival. 5 Besides the kinase activity, RIPK1 appears to have a scaffolding function, which may influence immune homeostasis. 6,7 Depending on the interacting partners and posttranslational modifications, RIPK1 has a multifaceted role in cell signaling and cell survival.8 Following TNF-R1 signaling, RIPK1 transitions between pro-survival and pro-cell death signaling complexes. 9,10 Necroptosis is a form of regulated necrosis of cells that operates in the absence of caspase activity 9 and is initiated by the engagement of various TLRs or cytokine receptors.11 The first cardinal signaling step in necrosome signaling is the phosphorylation of RIPK1, which leads to RIPK1-RIPK3 interaction and phosphorylation of RIPK3.12 Although necroptotic signaling has been shown to be...

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RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis

Cited by 289 publications

References 42 publications

TRAF2 is a biologically important necroptosis suppressor

TRAF2 is a biologically important necroptosis suppressor

Old, new and emerging functions of caspases

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

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