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Joanne A O'Donnell, Jesse Lehman, Justine E Roderick, Dalia Martinez-Marin, Matija Zelic, Ciara Doran, Nicole Hermance, Stephen Lyle, Manolis Pasparakis, Katherine A Fitzgerald, Ann Marshak-Rothstein, Michelle A Kelliher
No abstract text is available yet for this article.
March 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Fanxin Zeng, Xiao Chen, Weiyi Cui, Wei Wen, Fujian Lu, Xueting Sun, Dongwei Ma, Ye Yuan, Zezhong Li, Ning Hou, Hong Zhao, Xinyu Bi, Jianjun Zhao, Jianguo Zhou, Yan Zhang, Rui-Ping Xiao, Jianqiang Cai, Xiuqin Zhang
The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer (CRC) and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca2+ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca2+ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation...
March 12, 2018: Cancer Research
Xiaodong Cui, Ru Wang, Zhuanhua Wang
A cationic peroxidase (POD) was purified from proso millet seeds (PmPOD) using ammonium sulfate fractionation, cation exchange, and size exclusion chromatography. The purified PmPOD showed toxicity to normal cells and tumor cells, but was more sensitive in HT29 cells. Furthermore, the mechanism driving HCT116 and HT29 cell death by PmPOD was the induction of receptor interacting protein kinase 1 (RIPK1)- and RIPK3-dependent necroptosis, independent of apoptosis. More importantly, PmPOD could induce tumor necrosis factor-α (TNF-α) production through transcriptional upregulation...
March 12, 2018: Food & Function
Michal Lusthaus, Niv Mazkereth, Natalie Donin, Zvi Fishelson
The complement system participates in the pathogenesis of many diseases. Complement activation produces several active protein complexes and peptides, including the terminal C5b-9 complexes. It was reported that C5b-9 complexes insert into the plasma membrane and cause membrane perturbation, intracellular calcium surge, metabolic depletion, and osmotic lysis. Previously, we showed that complement-dependent cytotoxicity (CDC) is regulated by JNK and Bid. Here, we demonstrate that three mediators in TNFα-induced necroptosis (regulated necrosis), the receptor-interacting protein kinases, receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like protein (MLKL), are activated by complement and contribute to CDC...
2018: Frontiers in Immunology
Anne von Mässenhausen, Wulf Tonnus, Nina Himmerkus, Simon Parmentier, Danish Saleh, Diego Rodriquez, Jiraporn Ousingsawat, Rosalind L Ang, Joel M Weinberg, Ana B Sanz, Alberto Ortiz, Adrian Zierleyn, Jan Ulrich Becker, Blandine Baratte, Nathalie Desban, Stéphane Bach, Ina Maria Schiessl, Shoko Nogusa, Siddharth Balachandran, Hans Joachim Anders, Adrian T Ting, Markus Bleich, Alexei Degterev, Karl Kunzelmann, Stefan R Bornstein, Douglas R Green, Christian Hugo, Andreas Linkermann
Receptor-interacting protein kinases 1 and 3 (RIPK1/3) have best been described for their role in mediating a regulated form of necrosis, referred to as necroptosis. During this process, RIPK3 phosphorylates mixed lineage kinase domain-like (MLKL) to cause plasma membrane rupture. RIPK3-deficient mice have recently been demonstrated to be protected in a series of disease models, but direct evidence for activation of necroptosis in vivo is still limited. Here, we sought to further examine the activation of necroptosis in kidney ischemia-reperfusion injury (IRI) and from TNFα-induced severe inflammatory response syndrome (SIRS), two models of RIPK3-dependent injury...
March 2, 2018: Cell Death & Disease
R K Subbarao Malireddi, Prajwal Gurung, Jayadev Mavuluri, Tejasvi Krishna Dasari, Jeffery M Klco, Hongbo Chi, Thirumala-Devi Kanneganti
The NOD-like receptor (NLR)-P3 inflammasome is a global sensor of infection and stress. Elevated NLRP3 activation levels are associated with human diseases, but the mechanisms controlling NLRP3 inflammasome activation are largely unknown. Here, we show that TGF-β activated kinase-1 (TAK1) is a central regulator of NLRP3 inflammasome activation and spontaneous cell death. Absence of TAK1 in macrophages induced spontaneous activation of the NLRP3 inflammasome without requiring toll-like receptor (TLR) priming and subsequent activating signals, suggesting a distinctive role for TAK1 in maintaining NLRP3 inflammasome homeostasis...
March 2, 2018: Journal of Experimental Medicine
Mohammad Ali, Edward S Mocarski
Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis...
March 1, 2018: Cell Death & Disease
Oyuna S Kozhevnikova, Darya V Telegina, Vasiliy A Devyatkin, Nataliya G Kolosova
Age-related macular degeneration (AMD) is a complex neurodegenerative disease resulting in a loss of central vision in the elderly. It is currently assumed that impairment of autophagy may be one of the key mechanisms leading to AMD. Here we estimated the influence of age-related autophagy alterations in the retina on the development of AMD-like retinopathy in senescence-accelerated OXYS rats. Significant changes in the expression of the autophagy proteins were absent at the age preceding the development of retinopathy (age 20 days)...
February 28, 2018: Biogerontology
Lily Dara
The 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...
February 2018: Seminars in Liver Disease
Mark A Hawk, Cassandra L Gorsuch, Patrick Fagan, Chan Lee, Sung Eun Kim, Jens C Hamann, Joshua A Mason, Kelsey J Weigel, Matyas Abel Tsegaye, Luqun Shen, Sydney Shuff, Junjun Zuo, Stephan Hu, Lei Jiang, Sarah Chapman, W Matthew Leevy, Ralph J DeBerardinis, Michael Overholtzer, Zachary T Schafer
For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of ROS and cell viability during ECM detachment. We find that RIPK1 activation during ECM detachment results in mitophagy induction through a mechanism dependent on the mitochondrial phosphatase PGAM5...
March 2018: Nature Cell Biology
Alessandro Annibaldi, Sidonie Wicky John, Tom Vanden Berghe, Kirby N Swatek, Jianbin Ruan, Gianmaria Liccardi, Katiuscia Bianchi, Paul R Elliott, Sze Men Choi, Samya Van Coillie, John Bertin, Hao Wu, David Komander, Peter Vandenabeele, John Silke, Pascal Meier
Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation...
February 15, 2018: Molecular Cell
Mark Lötzerich, Pascal S Roulin, Karin Boucke, Robert Witte, Oleg Georgiev, Urs F Greber
Apoptosis and programmed necrosis (necroptosis) determine cell fate, and antagonize infection. Execution of these complementary death pathways involves the formation of receptor-interacting protein kinase 1 (RIPK1) containing complexes. RIPK1 binds to adaptor proteins, such as TRIF (Toll-IL-1 receptor-domain-containing-adaptor-inducing interferon-beta factor), FADD (Fas-associated-protein with death domain), NEMO (NF-κB regulatory subunit IKKγ), SQSTM1 (sequestosome 1/p62), or RIPK3 (receptor-interacting protein kinase 3), which are involved in RNA sensing, NF-κB signaling, autophagosome formation, apoptosis, and necroptosis...
February 15, 2018: Cell Death & Disease
Marinella G Callow, Colin Watanabe, Katherine E Wickliffe, Russell Bainer, Sarah Kummerfield, Julie Weng, Trinna Cuellar, Vasantharajan Janakiraman, Honglin Chen, Ben Chih, Yuxin Liang, Benjamin Haley, Kim Newton, Michael R Costa
The necroptotic cell death pathway is a key component of human pathogen defense that can become aberrantly derepressed during tissue homeostasis to contribute to multiple types of tissue damage and disease. While formation of the necrosome kinase signaling complex containing RIPK1, RIPK3, and MLKL has been extensively characterized, additional mechanisms of its regulation and effector functions likely remain to be discovered. We screened 19,883 mouse protein-coding genes by CRISPR/Cas9-mediated gene knockout for resistance to cytokine-induced necroptosis and identified 112 regulators and mediators of necroptosis, including 59 new candidate pathway components with minimal or no effect on cell growth in the absence of necroptosis induction...
February 15, 2018: Cell Death & Disease
Ji-Min Lee, Masahiro Yoshida, Mi-So Kim, June-Hyuk Lee, Ae-Rin Baek, An Soo Jang, Do Jin Kim, Shunsuke Minagawa, Su Sie Chin, Choon-Sik Park, Jun Araya, Kazuyoshi Kuwano, Sung Woo Park
RATIONALE: Alveolar epithelial cell (AEC) injury leading to cell death is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF). Among regulated/programmed cell death, the excessive apoptosis of AECs has been widely implicated in IPF pathogenesis. Necroptosis is a type of regulated/programmed necrosis. A multiprotein complex composed of receptor-interacting protein kinase-1 and -3 (RIPK1/3) plays a key regulatory role in initiating necroptosis. Although necroptosis participates in disease pathogeneses through the release of damage-associated molecular patterns (DAMPs), its association with IPF progression remains elusive...
February 14, 2018: American Journal of Respiratory Cell and Molecular Biology
Huyan Meng, Zhen Liu, Xingyan Li, Huibing Wang, Taijie Jin, Guowei Wu, Bing Shan, Dana E Christofferson, Chunting Qi, Qiang Yu, Ying Li, Junying Yuan
RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNFα, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II...
February 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Sam Hofmans, Lars Devisscher, Sofie Martens, Dries Van Rompaey, Kenneth Goossens, Tatyana Divert, Wim Nerinckx, Nozomi Takahashi, Hans De Winter, Pieter Van der Veken, Vera Goossens, Peter Vandenabeele, Koen Augustyns
Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Since tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors...
February 13, 2018: Journal of Medicinal Chemistry
Marietta Armaka, Caroline Ospelt, Manolis Pasparakis, George Kollias
NFκB activation and regulated cell death are important in tissue homeostasis, inflammation and pathogenesis. Here we show the role of the p55TNFR-IKK2l-Ripk3 axis in the regulation of synovial fibroblast homeostasis and pathogenesis in TNF-mediated mouse models of arthritis. Mesenchymal-specific p55TNFR triggering is indispensable for arthritis in acute and chronic TNF-dependent models. IKK2 in joint mesenchymal cells is necessary for the development of cartilage destruction and bone erosion; however, in its absence synovitis still develops...
February 12, 2018: Nature Communications
Sofie Martens, Vera Goossens, Lars Devisscher, Sam Hofmans, Polien Claeys, Marnik Vuylsteke, Nozomi Takahashi, Koen Augustyns, Peter Vandenabeele
The Aurora kinase family (Aurora A, B and C) are crucial regulators of several mitotic events, including cytokinesis. Increased expression of these kinases is associated with tumorigenesis and several compounds targeting Aurora kinase are under evaluation in clinical trials (a.o. AT9283, AZD1152, Danusertib, MLN8054). Here, we demonstrate that the pan-Aurora kinase inhibitor Tozasertib (VX-680 and MK-0457) not only causes cytokinesis defects through Aurora kinase inhibition, but is also a potent inhibitor of necroptosis, a cell death process regulated and executed by the RIPK1, RIPK3 and MLKL signalling axis...
February 12, 2018: Cell Death & Disease
Jacob J Briedé, Lize Deferme, Jarno E J Wolters, Sandra M H Claessen, Twan van den Beucken, J Richard Wagner, Simone G van Breda, Jos C S Kleinjans
Regulation of DNA methylation plays a crucial role in biological processes and carcinogenesis. The formation of 5-hydroxymethylcytosine (5hmC) by oxidation of 5-methylcytosine (5mC) has been proposed as an intermediate of active demethylation. However, whether and how active demethylation is regulated by oxidative stress-related processes is not well understood. Here we investigated whether free oxygen radicals are capable of directly forming 5hmC and how this enhanced whole genome gene expression. We applied LC-MS/MS technology for the analysis of 5mC, 5hmC, 5-formylcytosine (5fC) and 5-hydroxymethyluracyl (5hmU) in HepG2 cells exposed to hydroxyl- and methyl radicals, formed by tert-butyl hydroperoxide (TBH) at multiple time points...
February 9, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Hong Zhu, Aijun Sun
Programmed cell death plays an essential role in myocardial homeostasis and pathology. Three distinct forms of programmed cell death have been identified, namely apoptosis, necrosis, and autophagic cell death. Necrosis, previously known as an unregulated form of cell death, has been recognized as a highly regulated process now and attracted great attention over the past decade. Programmed necrosis mainly refers to necroptosis, pyroptosis, ferroptosis, and mitochondrial permeability transition (MPT)-dependent necrosis...
March 2018: Journal of Molecular and Cellular Cardiology
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