scholarly journals The scaffold-dependent function of RIPK1 in dendritic cells promotes injury-induced colitis

2021 ◽  
Author(s):  
Kenta Moriwaki ◽  
Christa Park ◽  
Kazuha Koyama ◽  
Sakthi Balaji ◽  
Kohei Kita ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Activity ◽  
Survival Function ◽  
Neutrophil Infiltration ◽  
Immune Homeostasis ◽  
Loss Of Function ◽  
Interacting Protein ◽  
Hematopoietic Stem ◽  
Bowel Diseases ◽  
Promote Cell Survival

AbstractReceptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and a perinatal lethality in Ripk1−/− mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain intestinal immune homeostasis. Here, we generated dendritic cell (DC)-specific Ripk1−/− mice in a genetic background with loss of RIPK1 kinase activity and found that the mice developed spontaneous colonic inflammation characterized by increased neutrophil infiltration. In addition, these mice were highly resistant to injury-induced colitis. The increased neutrophil infiltration in the colon and the resistance to colitis were restored by dual inactivation of RIPK3 and FADD, but not by inhibition of RIPK3, MLKL, or ZBP1 alone. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in protecting colonic DCs from apoptotic insults and maintenance of colonic immune homeostasis.

scholarly journals The scaffold-dependent function of RIPK1 in dendritic cells promotes injury-induced colitis

2021 ◽  
Author(s):  
Kenta Moriwaki ◽  
Christa Park ◽  
Kazuha Koyama ◽  
Sakthi Balaji ◽  
Kohei Kita ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Activity ◽  
Survival Function ◽  
Immune Homeostasis ◽  
Loss Of Function ◽  
Colonic Inflammation ◽  
Interacting Protein ◽  
Hematopoietic Stem ◽  
Bowel Diseases ◽  
Promote Cell Survival

AbstractReceptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and perinatal lethality in Ripk1−/− mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain intestinal immune homeostasis. Here, we generated dendritic cell (DC)-specific Ripk1−/− mice in a genetic background with loss of RIPK1 kinase activity and found that the mice developed spontaneous colonic inflammation characterized by increased neutrophil and Ly6C+ monocytes. In addition, these mice were highly resistant to injury-induced colitis. The increased colonic inflammation and the resistance to colitis were restored by dual inactivation of RIPK3 and FADD, but not by inhibition of RIPK3, MLKL, or ZBP1 alone. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in DC-mediated maintenance of colonic immune homeostasis.

scholarly journals Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

2018 ◽  
Vol 116 (3) ◽  
pp. 970-975 ◽  
Author(s):  
Yue Li ◽  
Marita Führer ◽  
Ehsan Bahrami ◽  
Piotr Socha ◽  
Maja Klaudel-Dreszler ◽  
...  
Keyword(s):  
Cell Death ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
Loss Of Function ◽  
Monogenic Disorders ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Human Immune

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

TNF-α/Fas-RIP-1–induced cell death signaling separates murine hematopoietic stem cells/progenitors into 2 distinct populations

Blood ◽  
2011 ◽  
Vol 118 (23) ◽  
pp. 6057-6067 ◽  
Author(s):  
Yechen Xiao ◽  
Hongling Li ◽  
Jun Zhang ◽  
Andrew Volk ◽  
Shubin Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Bone Marrow Failure ◽  
Caspase 8 ◽  
Apoptotic Pathway ◽  
Interacting Protein ◽  
Hematopoietic Stem ◽  
Complete Inactivation ◽  
Bone Marrow Failure Syndromes ◽  
Tnf Α

AbstractWe studied the effects of TNF-α and Fas-induced death signaling in hematopoietic stem and progenitor cells (HSPCs) by examining their contributions to the development of bone marrow failure syndromes in Tak1-knockout mice (Tak1−/−). We found that complete inactivation of TNF-α signaling by deleting both of its receptors, 1 and 2 (Tnfr1−/−r2−/−), can prevent the death of 30% to 40% of Tak1−/− HSPCs and partially repress the bone marrow failure phenotype of Tak1−/− mice. Fas deletion can prevent the death of 5% to 10% of Tak1−/− HSPCs but fails to further improve the survival of Tak1−/−Tnfr1−/−r2−/− HSPCs, suggesting that Fas might induce death within a subset of TNF-α-sensitive HSPCs. This TNF-α/Fas-induced cell death is a type of receptor-interacting protein-1 (RIP-1)–dependent programmed necrosis called necroptosis, which can be prevented by necrostatin-1, a specific RIP-1 inhibitor. In addition, we found that the remaining Tak1−/− HSPCs died of apoptosis mediated by the caspase-8–dependent extrinsic apoptotic pathway. This apoptosis can be converted into necroptosis by the inhibition of caspase-8 and prevented by inhibiting both caspase-8 and RIP-1 activities. We concluded that HSPCs are heterogeneous populations in response to death signaling stimulation. Tak1 mediates a critical survival signal, which protects against both TNF-α/Fas-RIP-1–dependent necroptosis and TNF-α/Fas-independent apoptosis in HSPCs.

scholarly journals NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation

2021 ◽  
Vol 4 (6) ◽  
pp. e202000956
Author(s):  
Snehlata Kumari ◽  
Trieu-My Van ◽  
Daniela Preukschat ◽  
Hannah Schuenke ◽  
Marijana Basic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Tumor Necrosis ◽  
Kinase Activity ◽  
Tumor Necrosis Factor Receptor ◽  
Skin Inflammation ◽  
Interacting Protein ◽  
Inflammatory Gene Expression ◽  
Underlying Mechanisms ◽  
Necrosis Factor

Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB–dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)–dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB–dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.

scholarly journals Systematic genetic mapping of necroptosis identifies SLC39A7 as modulator of death receptor trafficking

2018 ◽  
Author(s):  
Astrid Fauster ◽  
Manuele Rebsamen ◽  
Katharina L. Willmann ◽  
Adrian César-Razquin ◽  
Enrico Girardi ◽  
...  
Keyword(s):  
Cell Death ◽  
Death Receptor ◽  
Receptor Trafficking ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Genetic Screens ◽  
Gain Of Function ◽  
Interacting Protein ◽  
Knock Out ◽  
Unbiased Gene

ABSTRACTRegulation of cell and tissue homeostasis by programmed cell death is a fundamental process with wide physiological and pathological implications. The advent of scalable somatic cell genetic technologies creates the opportunity to functionally map these essential pathways, thereby identifying potential disease-relevant components. We investigated the genetic basis underlying necroptotic cell death by performing a complementary set of loss- and gain-of-function genetic screens. To this end, we established FADD-deficient haploid human KBM7 cells, which specifically and efficiently undergo necroptosis after a single treatment with either TNFα or the SMAC mimetic compound birinapant. A series of unbiased gene-trap screens identified key signaling mediators, such as TNFR1, RIPK1, RIPK3, and MLKL. Among the novel components, we focused on the zinc transporter SLC39A7, whose knock-out led to necroptosis resistance by affecting TNF receptor trafficking and ER homeostasis. Orthogonal, solute carrier (SLC)-focused CRISPR/Cas9-based genetic screens revealed the exquisite specificity of SLC39A7, among ~ 400 SLC genes, for TNFR1- and FAS-but not TRAIL-R1-mediated responses. The newly established cellular model also allowed genome-wide gain-of-function screening for genes conferring resistance to necroptosis via the CRISPR/Cas9 synergistic activation mediator approach. Among these, we found cIAP1 and cIAP2, and characterized the role of TNIP1 (TNFAIP3-interacting protein 1), which prevented pathway activation in a ubiquitin-binding dependent manner. Altogether, the gain- and loss-of-function screens described here provide a global genetic chart of the molecular factors involved in necroptosis and death receptor signaling, prompting investigation of their individual contribution and potential role in pathological conditions.

scholarly journals The Receptor Interacting Protein Kinases in the Liver

2018 ◽  
Vol 38 (01) ◽  
pp. 073-086 ◽  
Author(s):  
Lily Dara
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Kinase Activity ◽  
Cultured Cells ◽  
Interacting Protein ◽  
Regulated Cell Death ◽  
Cell Death Program ◽  
Cell Death Signaling ◽  
Experimental Liver ◽  
Mediate Inflammation

AbstractThe receptor interacting serine/threonine kinase1 and 3 (RIPK1, RIPK3) are regulators of cell death and survival. RIPK1 kinase activity is required for necroptosis and apoptosis, while its scaffolding function is necessary for survival. Although both proteins can mediate apoptosis, RIPK1 and RIPK3 are most well-known for their role in the execution of necroptosis via the mixed lineage domain like pseudokinase. Necroptosis is a caspase-independent regulated cell death program which was first described in cultured cells with unknown physiologic relevance in the liver. Many recent reports have suggested that RIPK1 and/or RIPK3 participate in liver disease pathogenesis and cell death. Notably, both proteins have been shown to mediate inflammation independent of cell death. Whether necroptosis occurs in hepatocytes, and how it is executed in the presence of an intact caspase machinery is controversial. In spite of this controversy, it is evident that RIPK1 and RIPK3 participate in many experimental liver disease models. Therefore, in addition to cell death signaling, their necroptosis-independent role warrants further examination.

scholarly journals Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock

2019 ◽  
Vol 116 (33) ◽  
pp. 16497-16506 ◽  
Author(s):  
Anthony Orvedahl ◽  
Michael R. McAllaster ◽  
Amy Sansone ◽  
Bria F. Dunlap ◽  
Chandni Desai ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Survival Function ◽  
Myeloid Cell ◽  
Critical Function ◽  
Interacting Protein ◽  
Autophagy Gene ◽  
Genome Wide

Host inflammatory responses must be tightly regulated to ensure effective immunity while limiting tissue injury. IFN gamma (IFNγ) primes macrophages to mount robust inflammatory responses. However, IFNγ also induces cell death, and the pathways that regulate IFNγ-induced cell death are incompletely understood. Using genome-wide CRISPR/Cas9 screening, we identified autophagy genes as central mediators of myeloid cell survival during the IFNγ response. Hypersensitivity of autophagy gene-deficient cells to IFNγ was mediated by tumor necrosis factor (TNF) signaling via receptor interacting protein kinase 1 (RIPK1)- and caspase 8-mediated cell death. Mice with myeloid cell-specific autophagy gene deficiency exhibited marked hypersensitivity to fatal systemic TNF administration. This increased mortality in myeloid autophagy gene-deficient mice required the IFNγ receptor, and mortality was completely reversed by pharmacologic inhibition of RIPK1 kinase activity. These findings provide insight into the mechanism of IFNγ-induced cell death via TNF, demonstrate a critical function of autophagy genes in promoting cell viability in the presence of inflammatory cytokines, and implicate this cell survival function in protection against mortality during the systemic inflammatory response.

scholarly journals Ferroptosis in Cancer Cell Biology

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 164 ◽  
Author(s):  
Christina M. Bebber ◽  
Fabienne Müller ◽  
Laura Prieto Clemente ◽  
Josephine Weber ◽  
Silvia von Karstedt
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Potential Role ◽  
Kinase Activity ◽  
Systemic Treatment ◽  
Interacting Protein ◽  
Tumour Immunology ◽  
Tumour Suppression ◽  
Regulated Necrosis ◽  
Review Current

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer.

scholarly journals Bcl-2 does not require Raf kinase activity for its death-protective function

1997 ◽  
Vol 324 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Reynald OLIVIER ◽  
Isabelle OTTER ◽  
Laurent MONNEY ◽  
Markus WARTMANN ◽  
Christoph BORNER
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Kinase Activity ◽  
Survival Function ◽  
Active Form ◽  
Signal Transduction Pathway ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Protective Function

It has been widely accepted that the oncogene product bcl-2 protects mammalian cells from programmed cell death (apoptosis). The molecules and signalling pathways upon which bcl-2 acts are, however, still ill-defined. Recently, bcl-2 was shown to interact with c-raf-1 in vitro. Furthermore, an active form of c-raf-1 delayed apoptosis induced by trophic factor deprivation and enhanced the death-suppressive function of bcl-2 when co-expressed. This has led to the hypothesis that bcl-2 communicates cell-death protection via a raf-dependent signal transduction pathway. Here we show, by various immunological and biochemical methods, that bcl-2 does not stably associate with c-raf-1 in cellular extracts prepared from fibroblasts before or after treatment with agents that induce apoptosis. Unexpectedly, bcl-2 function is entirely maintained, if not improved, when raf-dependent signalling is experimentally abrogated. In fact, bcl-2 allows the stable overexpression of a kinase-defective dominant-negative raf mutant that usually interferes with cell viability and/or proliferation. Our results indicate that bcl-2 does not require c-raf-1 kinase activity and an associated mitogen-activated protein kinase signalling pathway for its survival function. This property may be exploited to dissect cellular events that are dependent or independent of c-raf-1 kinase activity.

scholarly journals RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages

2020 ◽  
Author(s):  
Liang Tao ◽  
Yuguo Yi ◽  
Yuxin Chen ◽  
Haibing Zhang ◽  
Jiapeng Jie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Disease Progression ◽  
Kinase Activity ◽  
Inflammasome Activation ◽  
Deficient Diet ◽  
Interacting Protein ◽  
Sirius Red

AbstractHepatocyte cell death and liver inflammation have been well recognized as central characteristics of nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive. The kinase receptor-interacting protein 1 (RIP1) is a key regulator of apoptosis, necroptosis and inflammation, we thus hypothesized that the kinase activity of RIP1 may be involved in the pathogenesis of NASH. Wild-type and RIP1 kinase-dead (Rip1K45A/K45A) mice were fed with methionine-and choline-deficient diet (MCD) or high-fat diet (HFD) to establish distinct NASH models. In both models, compared to WT mice, Rip1K45A/K45A mice exhibited significantly less liver injury, less steatosis, decreased inflammation, and less cell death in liver tissue. Moreover, hepatic fibrosis as characterized by Sirius Red staining, expression of α-SMA and other fibrosis markers, were significantly alleviated in Rip1K45A/K45A mice than WT controls. Furthermore, using bone marrow transplantation to create chimeric mice, we found that it is the RIP1 kinase in hematopoietic-derived macrophages contributing mostly to the disease progression in NASH. Results from in vitro studies were in agreement with the in vivo data, demonstrating that RIP1 kinase was required for inflammasome activation and cell death induced by saturated fatty acid (palmitic acid) in bone marrow-derived macrophages (BMDMs). At last, we also found that the phosphorylation and expression of RIP1 was obviously increased in patients with NAFLD or NASH, but not in healthy controls. In summary, our results indicate that RIP1 kinase is activated during the pathogenesis of steatohepatitis, and consequently induces inflammation and cell death in macrophages, contributing to the disease progression. Our study suggests that macrophage RIP1 kinase represents a specific and potential target for the treatment of NASH.

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