RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation

Lin, Juan; Kumari, Snehlata; Kim, Chun; Van, Trieu-My; Wachsmuth, Laurens; Polykratis, Apostolos; Pasparakis, Manolis

doi:10.1038/nature20558

Cited by 322 publications

(374 citation statements)

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“…Importantly, the loss of ZBP1 prevented perinatal lethality in Ripk1 mRHIM mice, unveiling an unexpected role for RIPK1 in preventing ZBP1 dysregulation. In line with these findings, ZBP1 deficiency also prevented the development of skin lesions in mice with skin-specific depletion of RIPK1 (Ripk1 E-KO mice) or skin-specific expression of RIPK1 mRHIM (Ripk1 mRHIM/E-KO mice) [7]. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1 mRHIM , suggesting that the RIPK1 RHIM may prevent ZBP1 from binding and activating RIPK3 ( Figure 2B).…”

Section: Ripk1 Prevents Aberrant Zbp1-initiated Necroptosis Tom Vandesupporting

confidence: 73%

“…In the current issue of Nature, both the Pasparakis and Dixit Labs independently reveal that the absence of RIPK1 in the skin promotes a necrotic phenotype driven by ZBP1, a RHIM-containing protein that has previously been shown to mediate virus-induced necroptosis through activation of RIPK3/MLKL [6,7]. As a proof of concept, both groups generated mice expressing RIPK1 with an inactivating mutation (referred to as Ripk1 mRHIM mice) in the RHIM that abolishes the capacity of RIPK1 to interact with other cellular RHIM containing proteins.…”

Section: Ripk1 Prevents Aberrant Zbp1-initiated Necroptosis Tom Vandementioning

confidence: 99%

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2017

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Receptor interacting protein kinase 1 (RIPK1) regulates inflammation and cell death, in host defense and homeostasis. The adaptor function of RIPK1 allows pro-survival and inflammatory signaling, while its kinase activity regulates the induction of necroptosis and apoptosis. A new level of regulation through its RIP homotypic interaction motif (RHIM) was recently discovered to suppress necroptosis and inflammation driven by the putative nucleic acid sensor protein Z-DNA binding protein 1 (ZBP1), also known as DAI.In the two decades following the discovery of RIPK1, RIPK1 has emerged as a master regulator of inflammatory signaling and cell death [1]. To date, important advances in our understanding of RIPK1 function continue to be uncovered. RIPK1-deficient mice fail to thrive, die within 1-3 days following birth and display extensive apoptosis. These observations prompted initial research efforts to focus on the role of RIPK1 in controlling pro-survival and inflammatory gene expression. More recently, RIPK1 kinase activity emerged as essential for coordinating death receptorinduced necrosis ( Figure 1A). This type of necrosis was dubbed necroptosis upon the discovery of a chemical kinase inhibitor of RIPK1, necrostatin-1 (Nec1). However, the model of RIPK1 kinase functioning exclusively for necroptosis proved too simplistic as kinase activity was also found to be crucial for caspase 8-mediated apoptosis under conditions where cellular inhibitors of apoptosis (cIAPs) are depleted ( Figure 1A). Thus, depending on the cellular content, RIPK1 kinase can initiate either necroptosis or apoptosis. This implies that a protective phenotype observed in response to Nec1 or in the context of RIPK1 kinase dead knockin mice (Ripk1 KD mice) stems from the role of RIPK1 in regulating cell death but does not differentiate the cell death modality. Conditional deletion of RIPK1 in mice revealed additional complexity on the regulatory action of RIPK1. While absence of RIPK1 unleashes apoptosis in the intestinal epithelial cells [2,3], necroptotic cell death dominates in the skin upon RIPK1 depletion [3]. RIPK1 kinase dead knock-in mice did not show any spontaneous phenotype indicating the sensitization to apoptosis in the gut upon RIPK1 deletion Editorial: Autophagy and Cell DeathFigure 1: RIPK1 a master regulator of cell death and inflammation. A. Schematic representation of the versatile functions of RIPK1. Basically, RIPK1 regulates pro-survival and inflammatory signaling in addition to apoptotic and necroptotic cell death through its different regulatory domains viz. adaptor, kinase and RHIM docking function. B. Schematic representation of how the RHIM domain of RIPK1 acts as an essential break on constitutive ZBP1 activation. RIPK1 with an inactivating mutation in the RHIM that abolishes the capacity of RIPK1 to interact with other cellular RHIM containing proteins induces ZBP1/RIPK3/MLKL-mediated necroptosis and inflammation. This defect signaling results in a spontaneous phenotype in the mentioned RIPK1 transgenic mice, whic...

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Section: Ripk1 Prevents Aberrant Zbp1-initiated Necroptosis Tom Vandesupporting

confidence: 73%

Section: Ripk1 Prevents Aberrant Zbp1-initiated Necroptosis Tom Vandementioning

confidence: 99%

Untitled

2017

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“…In this study, we have addressed the role of RIPK1 kinase activity-dependent and -independent functions in liver homeostasis, hepatocyte death, and liver injury as well as in hepatocarcino- keratinocytes that undergo RIPK3-MLKL-dependent necroptosis, triggering skin inflammation (8,43). Therefore, apoptosis is the main pathway driving TNF-induced death in hepatocytes, likely due to the very low levels of RIPK3 expression in hepatocytes (44).…”

Section: Discussionmentioning

confidence: 99%

Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis

Van¹,

Polykratis²,

Straub³

et al. 2017

Journal of Clinical Investigation

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“…In our study, expression of RIPK1, RIPK3, and MLKL are low, specifically in neutrophils. Recent studies on proteins involved in necroptosis signaling (RIPK1, RIPK3, MLKL, cFLIP) suggest that suppression of inflammation or cell death involves RIPK1 [12, 31, 32]. …”

Section: Discussionmentioning

confidence: 99%

A Role for Receptor-Interacting Protein Kinase-1 in Neutrophil Extracellular Trap Formation in Patients with Systemic Lupus Erythematosus: a Preliminary Study

Guo

Xie

et al. 2018

Cell Physiol Biochem

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Background/Aims: Neutrophil extracellular traps (NETs) are known to play an important role in systemic lupus erythematosus (SLE) by triggering innate and adaptive immune responses. The molecular mechanisms responsible for their formation in SLE are still unclear. In this study, we aim to characterize the role of the receptor-interacting protein kinase-1 (RIPK1), a homologous serine/threonine kinase previously implicated in the regulation of necroptosis and tissue injury, in decreasing neutrophil death and formation of NETs, and to investigate the clinical implications of RIPK1 in SLE. Methods: Patients with SLE (n = 50) and healthy donors (n = 35) were enrolled in in vitro studies. Management of SLE patients was evaluated using the SLE disease activity index 2000 (SLEDAI-2K) score and laboratory variables. The mRNA level of RIPKs was measured by quantitative polymerase chain reaction (qPCR). Intracellular RIPK1 and RIPK3 production by peripheral blood leukocytes was detected by four-color flow cytometry and confirmed by automatic western blotting. TNF-α, IFN-γ, IL-1β, IL-2, IL-8, IL-18, and RIPK1 were measured by enzyme-linked immunosorbent assay. Cell death was assayed by Sytox green dye from peripheral neutrophils stimulated by RIPK-1-stabilizer necrostatin-1 (nec-1) and phorbol 12-myristate 13-acetate (PMA). Immunofluorescence staining and confocal microscopy were used to detect NET formation ex vivo. Quantification of NETs was determined by fluorescence spectrometry. Results: IFN-γ, IL-1β, IL-8, and IL-18 levels in serum were increased in SLE patients compared to controls. However, the expression of TNF-α, IL-2, and RIPK1 were decreased. In addition, we observed significant differences in the expression of RIPK1 in peripheral blood leukocytes. Of all the leukocytes, RIPK1 expression was significantly lower in neutrophils. Furthermore, we studied NETs formation in neutrophils of SLE with decreased RIPK1 expression, and these show increased susceptibility to NETosis, when stimulated with PMA and/or nec-1. Importantly, RIPK1 expression in neutrophils negatively correlated with ESR, CRP, 24-hour urine total protein, and the disease activity index in SLE. Conclusion: These data represent the first report of decreased RIPK1 expression in neutrophils of SLE patients and imply that RIPK1 may be involved in neutrophil death and NET formation. We suggest that RIPK1 is a potential biomarker to predict disease activity.

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RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation

Cited by 322 publications

References 32 publications

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Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis

A Role for Receptor-Interacting Protein Kinase-1 in Neutrophil Extracellular Trap Formation in Patients with Systemic Lupus Erythematosus: a Preliminary Study

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