Cell death articles within Nature Communications

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  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    The unfolded protein response (UPR) promotes cell survival in cancers with hyperactive ER stress response. Here the authors show that CARM1, an arginine methyltransferase, controls the IRE1α/XBP1 pathway of the UPR and the inhibition of this pathway can inhibit growth in CARM1 expressing ovarian cancers.

    • Jianhuang Lin
    • , Heng Liu
    •  & Rugang Zhang

  • Article
    | Open Access

    Cell death is a critical process in health and disease, yet available markers record later stages of cell death once a cell has already begun to decompose. Here the authors show the use of a genetically encoded calcium indicator that demarcates an irreversible stage of cell death earlier than previously possible.

    • Jeremy W. Linsley
    • , Kevan Shah
    •  & Steven Finkbeiner

  • Article
    | Open Access

    Cholesterol metabolism is involved in the progression of aggressive prostate cancer (PCa). Here the authors show that miR-205 downregulation promotes cholesterol synthesis and androgen receptor signalling in PCa through enhancing the expression of the rate-limiting enzyme of cholesterol synthesis, squalene epoxidase.

    • C. Kalogirou
    • , J. Linxweiler
    •  & A. Schulze

  • Article
    | Open Access

    Diabetes is characterized by dysfunction and loss of beta-cells, and promoting beta-cell survival is of therapeutic interest. Here the authors show that Large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, induces beta-cell failure through mTORC1 hyperactivation and autophagic flux suppression.

    • Ting Yuan
    • , Karthika Annamalai
    •  & Amin Ardestani

  • Article
    | Open Access

    UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.

    • Davide Pradella
    • , Gianluca Deflorian
    •  & Claudia Ghigna

  • Article
    | Open Access

    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

  • Comment
    | Open Access

    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

  • Article
    | Open Access

    The serine/threonine kinase WNK1 is an inhibitor of chloride efflux. Here the authors show that this inhibition is a means of negatively regulating the activation of the NLRP3 inflammasome in macrophages, leading to reduced inflammatory responses.

    • Lindsey Mayes-Hopfinger
    • , Aura Enache
    •  & Emad S. Alnemri

  • Article
    | Open Access

    Necroptosis, a form of cell death, occurs in acute renal injury. Here, the authors show that ferroptosis—a form of cell death dependent on iron - also occurs during acute kidney injury, and show that an inhibitor of ferroptosis can improve survival in a mouse model of acute kidney damage.

    • Wulf Tonnus
    • , Claudia Meyer
    •  & Andreas Linkermann

  • Article
    | Open Access

    The small molecule DNMDP acts as a velcrin by inducing complex formation between phosphodiesterase PDE3A and SLFN12, which kills cancer cells that express sufficient levels of both proteins. Here, the authors present the cryo-EM structure of the DNMDP-stabilized PDE3A-SLFN12 complex and show that SLFN12 is an RNase. PDE3A binding increases SLFN12 RNase activity, and SLFN12 RNase activity is required for DNMDP-mediated cancer cell killing.

    • Colin W. Garvie
    • , Xiaoyun Wu
    •  & Heidi Greulich

  • Article
    | Open Access

    Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome characterized by severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here the authors introduce a human SGS model that displays disease-relevant phenotypes to demonstrate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.

    • Federica Banfi
    • , Alicia Rubio
    •  & Alessandro Sessa

  • Article
    | Open Access

    Iron is essential during pregnancy for embryo and placental development and maternal health. However, in this study using mouse models, the authors demonstrate that excess maternal iron causes adverse embryo outcomes in pregnancies with underlying systemic inflammation.

    • Allison L. Fisher
    • , Veena Sangkhae
    •  & Elizabeta Nemeth

  • Article
    | Open Access

    p53 is able to induce ferroptosis in response to reactive oxygen species (ROS)-induced stress and suppresses tumour growth. Here, the authors show that iPLA2β suppresses p53-medated ferroptosis by cleaving and detoxifying peroxidized lipids and that this is independent of canonical ferroptosis regulator GPX4.

    • Delin Chen
    • , Bo Chu
    •  & Wei Gu

  • Article
    | Open Access

    Controlled cell death can be an efficient anti-viral strategy, but also leads to tissue damage and needs to be balanced. Oyler-Yaniv et al. combine mathematical modelling and microscopy to show that exposure to TNF in response to viral infection causes cells to tune their speed-vs-accuracy trade-off in cell death decision to limit HSV-1 spread.

    • Jennifer Oyler-Yaniv
    • , Alon Oyler-Yaniv
    •  & Roy Wollman

  • Article
    | Open Access

    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

  • Article
    | Open Access

    DEAD-box polypeptide 3 (DDX3) is a host protein belonging to the family of ATP-dependent RNA helicases. Here, the authors demonstrate that DDX3 inhibitors reverse HIV-1 latency and selectively induce cell death in HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1.

    • Shringar Rao
    • , Cynthia Lungu
    •  & Tokameh Mahmoudi

  • Article
    | Open Access

    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

  • Article
    | Open Access

    The high degree of subtype plasticity in small cell lung cancer (SCLC) poses a therapeutic challenge. Here, the authors show that the non-neuroendocrine (non-NE) subtype of SCLC is sensitive to ferroptosis while the neuroendocrine (NE) subtype is vulnerable to TRX anti-oxidant pathway inhibition, and the combination of these two treatments in SCLC circumvents non-NE/NE subtype plasticity.

    • Christina M. Bebber
    • , Emily S. Thomas
    •  & Silvia von Karstedt

  • Article
    | Open Access

    The BCL-2 family protein BAX functions to regulate mitochondria-driven cell death. Here the authors show that the drug Eltrombopag inhibits BAX and prevents apoptosis induced by cytotoxic stimuli.

    • Adam Z. Spitz
    • , Emmanouil Zacharioudakis
    •  & Evripidis Gavathiotis

  • Article
    | Open Access

    The core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP, coordinate cell fate. Here authors present the structure of full-length procaspase-8 in a complex with FADD and reveal how recruitment of c-FLIPS into this complex inhibits Caspase-8 activity.

    • Joanna L. Fox
    • , Michelle A. Hughes
    •  & Marion MacFarlane

  • Article
    | Open Access

    Ferroptosis is an iron-dependent form of oxidative cell death. In this study, the authors show that NUPR1, a stress-inducible transcription factor, may be a driver of ferroptosis resistance.

    • Jiao Liu
    • , Xinxin Song
    •  & Daolin Tang

  • Article
    | Open Access

    Cell extrusion regulates monolayer cell density and is critical in maintaining epithelia integrity, which has implications in homeostasis, development, and cancer progression. Here the authors describe how monolayer integrate mechanical signals from tissue mechanics, cell-cell adhesion, cell-substrate adhesion and cytoskeleton coordinate cell extrusion.

    • Anh Phuong Le
    • , Jean-François Rupprecht
    •  & Benoît Ladoux

  • Article
    | Open Access

    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

  • Article
    | Open Access

    Although executioner caspase activation is considered terminal, some cells are capable of survival, suggesting additional regulation. Here, the authors show that cells in the Drosophila wing imaginal disc survive caspase activation via Akt1 and dCIZ1 and actively participate in tissue regeneration.

    • Gongping Sun
    • , Xun Austin Ding
    •  & Denise J. Montell

  • Article
    | Open Access

    Glaucoma is the leading cause of irreversible blindness affecting over 70 million people worldwide. Here, the authors show that inhibition of chronic ER stress-induced ATF4-CHOP-GADD34 signaling pathway rescues pathology in mouse models of glaucoma, thus suggesting a possible treatment strategy.

    • Ramesh B. Kasetti
    • , Pinkal D. Patel
    •  & Gulab S. Zode

  • Article
    | Open Access

    Calcium flux must be carefully controlled during the phagocytosis of apoptotic cells (efferocytosis), although how this occurs is not fully understood. Here, the authors show that the Cereblon E3 ligase regulates Orai1 degradation and subsequently SOCE-mediated calcium influx.

    • Hyunji Moon
    • , Chanhyuk Min
    •  & Daeho Park

  • Article
    | Open Access

    Tumour necrosis is associated with tumour aggressiveness and poor outcomes in patients with glioblastomas, but the underlying mechanisms remain poorly understood. Here, the authors show that in a xenograft mouse model of glioblastoma, tumour-infiltrating neutrophils amplify necrosis by promoting myeloperoxidase-induced tumour cell ferroptosis.

    • Patricia P. Yee
    • , Yiju Wei
    •  & Wei Li

  • Article
    | Open Access

    HMGB1 is an inflammatory mediator released by a variety of cell types. Here, the authors show that unlike IL-1β, HMGB1 is released non-specifically following cell lysis.

    • Allen Volchuk
    • , Anna Ye
    •  & Neil M. Goldenberg

  • Article
    | Open Access

    Mandibuloacral dysplasias (MADs) are rare progeroid syndromes characterized by nuclear morphological and functional abnormalities. Here the authors report that loss of mitochondrial membrane protein MTX2 causes a progeroid MAD sharing clinical features with lamin-associated progeroid syndromes.

    • Sahar Elouej
    • , Karim Harhouri
    •  & Annachiara De Sandre-Giovannoli

  • Article
    | Open Access

    Impaired oligodendrocyte (OL) differentiation and remyelination after myelin damage in multiple sclerosis is associated with neurodegeneration. The authors show that Gsta4 is expressed during adult OL differentiation and identify it as a regulator of OL differentiation, survival, and remyelination.

    • Karl E. Carlström
    • , Keying Zhu
    •  & Fredrik Piehl

  • Article
    | Open Access

    Programmed cell death or apoptosis is an essential biological process that is impaired in some diseases and can be used to assess the effectiveness of drugs. Here the authors design Apo-15 as a fluorogenic peptide for the detection and real-time imaging of apoptotic cells.

    • Nicole D. Barth
    • , Ramon Subiros-Funosas
    •  & Marc Vendrell

  • Article
    | Open Access

    It is unclear whether 2D metal dichalcogenides (TMD) alone can cause ferroptotic cell death. Here, the authors show TMD nanosheets induced ferroptosis in mammalian cell lines and in a mouse model after aspiration of TMD materials into lungs, causing ferroptotic cell death.

    • Shujuan Xu
    • , Huizhen Zheng
    •  & Ruibin Li

  • Article
    | Open Access

    Mitochondrial apoptosis is controlled by BCL2 family proteins, and the BH3-only proteins often act as sensors that transmit apoptotic signals. Here the authors show how the BH3-only proteins BMF and HRK can directly activate the BCL2 protein BAK and interact with BAK through an alternative binding groove.

    • Kaiqin Ye
    • , Wei X. Meng
    •  & Haiming Dai

  • Article
    | Open Access

    PDE3A modulators for cancer therapy cause serious side effects as they inhibit PDE3A phosphodiesterase activity, which is essential for the maturation of oocytes and the formation of platelets. Here, the authors identify a compound, nauclefine, that does not inhibit PDE3A activity but induces apoptosis by enabling a complex formation between PDE3A and SLFN12.

    • Youwei Ai
    • , Haibing He
    •  & Xiangbing Qi

  • Article
    | Open Access

    Retinal vein occlusion can cause blindness, and features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here the authors report a non-apoptotic role of endothelial caspase-9 in regulating blood-retina barrier integrity and neuronal survival, which can be therapeutically targeted in a mouse model of retinal vein occlusion.

    • Maria I. Avrutsky
    • , Crystal Colón Ortiz
    •  & Carol M. Troy

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