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| Open AccessA common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.
- Sarah E. Garnish
- , Katherine R. Martin
- & Joanne M. Hildebrand
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Article
| Open AccessA cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses
Different types of lytic cell death can trigger an anti-tumor immune response. Here the authors report the design of a near infrared light controllable micron-scale oncolytic system, triggering lipid peroxidation and lytic cell death in tumors as well anti-tumor immunity in preclinical cancer models.
- Zhigui Zuo
- , Hao Yin
- & Qinyang Wang
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Article
| Open AccessThe transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice
Aggravation of liver steatosis shifts the hepatocellular death mode from apoptosis to necroptosis in acute and chronic liver damage. Here the authors report that the transcription factor ATF3 regulates this shift through the induction of RIPK3, a regulator of necroptosis.
- Yuka Inaba
- , Emi Hashiuchi
- & Hiroshi Inoue
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Article
| Open AccessTyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulator of cell death pathways during embryogenesis and in infection/inflammation. Here authors show that tyrosine phosphorylation of RIPK1 by upstream kinases limits systemic inflammation and regulates haematopoietic homeostasis.
- Hailin Tu
- , Weihang Xiong
- & Xin Lin
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Article
| Open AccessTargeting necroptosis in muscle fibers ameliorates inflammatory myopathies
Polymyositis (PM) is a chronic inflammatory myopathy characterized by progressive muscle weakness. Here the authors showed that muscle fibers in PM undergo necroptosis and aggravate inflammation via releasing pro-inflammatory molecules such as HMGB1.
- Mari Kamiya
- , Fumitaka Mizoguchi
- & Shinsuke Yasuda
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| Open AccessRIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis
RIPK1 regulates inflammation and cell death and is inhibited by phosphorylation on numerous residues. Here, the authors use a CRISPR whole genome screen to identify that protein phosphatase 1 regulatory subunit 3G regulates RIPK1 apoptotic and necroptotic activity as well as inflammation.
- Jingchun Du
- , Yougui Xiang
- & Zhigao Wang
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Article
| Open AccessHuman RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis
The pseudokinase MLKL is activated by the upstream kinase RIPK3 in the necroptotic pathway but the structural basis of MLKL activation is not well understood yet. Here, the authors present the crystal structures of the human RIPK3:MLKL complex and human RIPK3 kinase alone, which reveal structural differences between human and murine RIPK3 and they discuss mechanistic implications.
- Yanxiang Meng
- , Katherine A. Davies
- & James M. Murphy
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Article
| Open AccessOTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity
OTULIN is a deubiquitinase for linear ubiquitin chains. Here the authors show, using genetic mouse models and single-cell RNA-sequencing, that deficiency of OTULIN in keratinocytes causes skin inflammation and verrucous carcinoma via the induction of keratinocyte death, thereby implicating a function of OTULIN in keratinocyte homeostasis.
- Esther Hoste
- , Kim Lecomte
- & Geert van Loo
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Article
| Open AccessOTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice
OTULIN is a negative regulator of linear ubiquitination, and its deficiency in human causes multi-organ inflammations including the skin. Here the authors show, by combining various genetic tools with epidermis-specific Otulin knockout mice, that Otulin suppresses skin inflammation predominantly by inhibiting RIPK1-mediated keratinocytes necroptosis.
- Hannah Schünke
- , Ulrike Göbel
- & Manolis Pasparakis
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Article
| Open AccessOPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection
During herpesvirus infection, most individuals intrinsically suppress a primary infection and therewith preclude potential damage or neurodegeneration of the CNS. Here, Ames et al. show that Optineurin (OPTN), a conserved autophagy receptor, restricts HSV-1 spread, degrades viral VP16 through autophagy and is neuroprotective against HSV infection in vivo.
- Joshua Ames
- , Tejabhiram Yadavalli
- & Deepak Shukla
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Article
| Open AccessNEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation
NEK1 mutations promote lethality early in life and ALS late in life via unknown mechanisms. Here, the authors show that NEK1 mutation disrupts retromer-mediated trafficking and promotes RIPK1 activation, connecting retromer trafficking and metabolism to neuroinflammation by dietary intervention.
- Huibing Wang
- , Weiwei Qi
- & Junying Yuan
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| Open AccessMultifaceted mechanisms mediating cystine starvation-induced ferroptosis
The cyst(e)ine/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis is the most frequently targeted pathway to trigger the ferroptosis cascade and suppress tumor growth. Two recent studies present additional mechanisms underlying cystine starvation-induced ferroptosis apart from impaired GSH synthesis.
- Zhennan Shi
- , Nathchar Naowarojna
- & Yilong Zou
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Article
| Open AccessUbiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance
Necroptosis is a form of cell death characterized by membrane rupture via MLKL oligomerization, although mechanistic details remain unclear. Here, the authors show that MLKL ubiquitylation of K219 facilitates high-order membrane assembly and subsequent rupture, promoting cytotoxicity.
- Laura Ramos Garcia
- , Tencho Tenev
- & Pascal Meier
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Article
| Open AccessZBP1 not RIPK1 mediates tumor necroptosis in breast cancer
Tumour necroptosis is regulated by RIPK3 during tumour development. Here the authors show that ZBP1 is an upstream mediator of RIPK3 in tumour necroptosis and that glucose deprivation induces the release of mitochondrial DNA, which binds to ZBP1 to activate ZBP1-mediated necroptosis in breast cancer.
- Jin Young Baik
- , Zhaoshan Liu
- & Zheng-gang Liu
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Article
| Open AccessConformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis
Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase is phosphorylated by RIPK3 kinase prior to cell death by necroptosis. Here, the authors use monobodies that bind to the MLKL pseudokinase domain as tools, which allowed them to determine the crystal structures of the MLKL pseudokinase domain in two distinct conformations. By combining their structural data with cell signalling assays and MD simulations they provide evidence that endogenous MLKL preassociates with its upstream regulator RIPK3, and that MLKL disengages from RIPK3 following the induction of necroptosis.
- Sarah E. Garnish
- , Yanxiang Meng
- & James M. Murphy
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Article
| Open AccessThe amyloid structure of mouse RIPK3 (receptor interacting protein kinase 3) in cell necroptosis
Receptor Interacting Protein Kinase 3 (RIPK3) has a key role in TNF-induced necroptosis. Here, the authors combine solid state NMR measurements, MD simulations and cell based assays to characterize mouse RIPK3 and they present the structure of the RIPK3 amyloid core.
- Xia-lian Wu
- , Hong Hu
- & Jun-xia Lu
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Article
| Open AccessUbiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
RIPK1 is a critical kinase which mediates necroptosis, apoptosis and inflammation. Regulation of RIPK1 by ubiquitination is being intensively investigated. Here, the authors made knock-in RIPK1-K612R mice and demonstrate that this mutation alters the RIPK1 ubiquitinylation pattern and inhibits its prodeath kinase activity in response to TNFα but sensitizes cell death to TLRs signals.
- Xingyan Li
- , Mengmeng Zhang
- & Junying Yuan
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Article
| Open AccessMLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis
Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. Here the authors show that MLKL trafficking and plasma membrane accumulation are crucial necroptosis checkpoints, and that accumulation of phosphorylated MLKL at intercellular junctions promotes necroptosis.
- Andre L. Samson
- , Ying Zhang
- & James M. Murphy
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Article
| Open AccessDistinct pseudokinase domain conformations underlie divergent activation mechanisms among vertebrate MLKL orthologues
The necroptotic cell death pathway involves signaling through pseudokinases. Here the authors define the structural determinants of species specificity in necroptosis signaling mediated by the essential necroptotic effector pseudokinase, Mixed Lineage Kinase Domain-Like (MLKL).
- Katherine A. Davies
- , Cheree Fitzgibbon
- & James M. Murphy
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Article
| Open AccessA missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction
Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.
- Joanne M. Hildebrand
- , Maria Kauppi
- & John Silke
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Article
| Open AccessAutophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation
Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses. Here the authors show that autophosphorylation at Ser166 is required for RIPK1-mediated cell death and inflammation in mouse models of inflammatory pathologies, making Ser166 phosphorylation a possible biomarker for RIPK1-mediated inflammatory diseases.
- Lucie Laurien
- , Masahiro Nagata
- & Manolis Pasparakis
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Article
| Open AccessDisruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis
Acid-sensing ion channel 1a (ASIC1a) mediates acidic neuronal necroptosis via recruiting receptor-interacting protein kinase 1 (RIPK1). Here authors show that auto-inhibition of ASICa prevents RIPK1 recruitment and demonstrate that targeting the auto-inhibition has therapeutic potential to prevent acidotoxicity.
- Jing-Jing Wang
- , Fan Liu
- & Tian-Le Xu
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Article
| Open AccessUbiquitination of RIPK1 suppresses programmed cell death by regulating RIPK1 kinase activation during embryogenesis
RIPK1 integrates signals that drive both NF-κB activation and cell death pathways. Here Zhang et al. generate RIPK1 knock-in mice lacking a major ubiquitination site and demonstrate that this modification is important to suppress cell death during embryogenesis and inflammation postnatally.
- Xixi Zhang
- , Haiwei Zhang
- & Haibing Zhang
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Article
| Open AccessSerine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
RIPK1 kinase activity is known to transduce a death signal, but the molecular mechanisms that normally prevent RIPK1 activation are unclear. Here, the authors report that IKK-mediated phosphorylation on RIPK1 Ser25 directly represses its enzymatic activity and thus RIPK1-dependent cell death.
- Yves Dondelinger
- , Tom Delanghe
- & Mathieu J. M. Bertrand
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Article
| Open AccessGasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation
Gasdermins mediate lytic cell death by forming pores in the plasma membrane. Here the authors show that gasdermins also permeabilize mitochondrial membrane, thereby facilitating intrinsic apoptosis pathway, downstream of apoptotic (Gasdermin E) and inflammatory (Gasdermin D) caspase activation.
- Corey Rogers
- , Dan A. Erkes
- & Emad S. Alnemri
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Article
| Open AccessA FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs
Necroptotic cells activate MLKL and release inflammatory DAMPs, although the underlying regulatory mechanisms of this process are poorly understood. Here, Murai et al. develop a necroptosis-specific FRET sensor (SMART) that monitors MLKL membrane translocation to identify two modes of DAMP release.
- Shin Murai
- , Yoshifumi Yamaguchi
- & Hiroyasu Nakano
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Article
| Open AccessLUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
TNF mediated inflammation is critical in autoimmune mediated pathology, however many patients are refractory to current anti-TNF therapeutics. Here the authors show induction of several death ligands, in addition to TNF is sufficient to cause fatal dermatitis in a LUBAC deficient murine model of disease.
- Lucia Taraborrelli
- , Nieves Peltzer
- & Henning Walczak
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Article
| Open AccessNecroptosis mediates myofibre death in dystrophin-deficient mice
Muscular dystrophies are characterised by extensive myofibre cell death. Here Morgan et al. show that RIPK3-mediated necroptosis contributes to myofibre cell death in Duchenne muscular dystrophy, and that RIPK3 deletion protects dystrophic mice against myofibre degeneration.
- Jennifer E. Morgan
- , Alexandre Prola
- & Maximilien Bencze
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Article
| Open AccessConformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis
RIPK3-mediated phosphorylation of the mixed lineage kinase domain-like (MLKL) pseudokinase is thought to be the trigger for MLKL activation during necroptotic signaling. Here the authors provide evidence that the transition of human MLKL from a monomeric state to a tetramer is essential for necroptosis signalling.
- Emma J. Petrie
- , Jarrod J. Sandow
- & James M. Murphy
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Article
| Open AccessPandemic H1N1 influenza A viruses suppress immunogenic RIPK3-driven dendritic cell death
The differences in virus-host interactions resulting in distinct pathogenicity of seasonal and pandemic influenza A viruses (IAV) are not well understood. Here, the authors show that the hemagglutinin segment from pandemic, but not seasonal, IAV suppresses RIPK3-mediated dendritic cell death, thereby reducing T cell activation.
- Boris M. Hartmann
- , Randy A. Albrecht
- & Stuart C. Sealfon
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Article
| Open AccessA novel Fer/FerT targeting compound selectively evokes metabolic stress and necrotic death in malignant cells
The tyrosine-kinases Fer/FerT associate with the mitochondrial electron transport chain in cancer cells supporting their metabolic reprogramming. Here the authors discover a compound that disrupts Fer /FerT activity and selectively induces cell death of cancer cell lines displaying anti-tumor activity in vivo.
- Yoav Elkis
- , Moshe Cohen
- & Uri Nir
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Article
| Open AccessThe cytoplasmic nuclear receptor RARγ controls RIP1 initiated cell death when cIAP activity is inhibited
The molecular switch between how tumour necrosis factor (TNF) controls inflammation versus cell death is less well defined. Here, the authors show that the nuclear receptor retinoic acid receptor gamma is released from the nucleus to disrupt TNF initiated cell death complexes in the cytoplasm.
- Qing Xu
- , Siriporn Jitkaew
- & Zheng-gang Liu
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Article
| Open AccessRegulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis
TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.
- Jiefei Geng
- , Yasushi Ito
- & Junying Yuan
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Article
| Open AccessRIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome
Mitochondrial reactive oxygen species (ROS) promote necroptosis and the receptor interacting protein 1 (RIP1) is a key player in this form of cell death. Here, the authors show that cysteine residues in RIP1 sense ROS and oxidation of the cysteines triggers RIP1 autophosphorylation, which promotes functional necrosome formation.
- Yingying Zhang
- , Sheng Sean Su
- & Jiahuai Han
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Article
| Open AccessThe necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance
The kinase RIPK3 initiates necroptosis, which has been reported to promote inflammation in various pathological conditions. Here, the authors show that genetic ablation of Ripk3results in adipocyte apoptosis and white adipose tissue inflammation in obese mice, which promotes glucose intolerance.
- Jérémie Gautheron
- , Mihael Vucur
- & Tom Luedde
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Article
| Open AccessCytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis
Kidney stone disease is caused by accumulation of oxalate crystals, which trigger tissue injury, inflammation and cell death. Mulay et al. show that crystals induce cell death in the kidney through necroptosis, and propose that this pathway may be a target for the treatment of crystal-induced disease.
- Shrikant R. Mulay
- , Jyaysi Desai
- & Hans-Joachim Anders
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Article |
The oncogenic microRNA miR-21 promotes regulated necrosis in mice
The microRNA miR-21 is overexpressed in cancer and is thought to function through anti-apoptotic activity. Here, Ma et al. show that deleting or blocking miR-21 in mice protects against acute pancreatitis and TNF-α-induced tissue damage by inhibiting RIP3-dependent regulated necrosis (necroptosis).
- Xiaodong Ma
- , Daniel J. Conklin
- & Yong Li
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Article
| Open AccessRIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL
RIPK3 can cause necroptotic cell death via MLKL phosphorylation, and activate NLRP3 inflammasome. Here the authors show that MLKL is dispensable for NLRP3 activation by RIPK3, and highlight how different IAP proteins limit RIPK3 induced apoptosis, necroptosis and IL-1 secretion.
- Kate E. Lawlor
- , Nufail Khan
- & James E. Vince
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Article |
Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis
Fas-associated protein with death domain (FADD) is part of a signalling complex that controls some forms of programmed cell death. Lee and colleagues demonstrate that FADD ubiquitination by the E3 ubiquitin ligase MKRN1 regulates FADD protein stability and thereby cell death.
- Eun-Woo Lee
- , Jung-Hoon Kim
- & Jaewhan Song