Succination inactivates gasdermin D and blocks pyroptosis
Fiachra Humphries,Liraz Shmuel-Galia,Natália Ketelut-Carneiro,Sheng Li,Bingwei Wang,Venkatesh V. Nemmara,Ruth Wilson,Zhaozhao Jiang,Farnaz Khalighinejad,Khaja Muneeruddin,Scott A. Shaffer,Ranjan Dutta,Carolina Ionete,Scott Pesiridis,Shuo Yang,Paul R. Thompson,Katherine A. Fitzgerald +16 more
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TLDR
In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD, revealing a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.Abstract:
Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.read more
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Journal ArticleDOI
Pyroptosis: mechanisms and diseases.
TL;DR: It is described that pyroptosis is a double-edged sword for tumors and the rational use of this dual effect will help to further explore the formation and development of tumors, and provide ideas for patients to develop new drugs based on pyroPTosis.
Journal ArticleDOI
Channelling inflammation: gasdermins in physiology and disease.
Xing Liu,Shiyu Xia,Shiyu Xia,Zhibin Zhang,Zhibin Zhang,Hao Wu,Hao Wu,Judy Lieberman,Judy Lieberman +8 more
TL;DR: The role of gasmin proteins in pyroptosis was discussed in this article, focusing on their mechanisms of action and roles in normal physiology and disease, and developing drugs to modulate gasminer activity to reduce inflammation or activate more potent immune responses.
FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation
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Redox regulation of immunometabolism.
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Inflammasome activation at the crux of severe COVID-19.
TL;DR: In this article, the authors review evidence that SARS-CoV-2 directly or indirectly activates inflammasomes, which are large multiprotein assemblies that are broadly responsive to pathogen-associated and stress-associated cellular insults, leading to secretion of the pleiotropic IL-1 family cytokines (IL-1β and IL-18), and pyroptosis, an inflammatory form of cell death.
References
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Journal ArticleDOI
Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death
Jianjin Shi,Yue Zhao,Kun Wang,Xuyan Shi,Wang Yue,Huanwei Huang,Yinghua Zhuang,Tao Cai,Fengchao Wang,Feng Shao +9 more
TL;DR: Gasdermin D (Gsdmd) is identified by genome-wide clustered regularly interspaced palindromic repeat-Cas9 nuclease screens of caspase-11- and caspasing-1-mediated pyroptosis in mouse bone marrow macrophages to offer insight into inflammasome-mediated immunity/diseases and change the understanding of pyroPTosis and programmed necrosis.
Journal ArticleDOI
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Gillian M. Tannahill,Anne M. Curtis,Juraj Adamik,Eva M. Palsson-McDermott,Anne F. McGettrick,Gautam Goel,Christian Frezza,Nicholas J. Bernard,Beth Kelly,Niamh Foley,Liang Zheng,A. Gardet,Zhen Tong,S. S. Jany,Sinéad C. Corr,Moritz Haneklaus,Brian E. Caffrey,Kerry A. Pierce,Sarah R. Walmsley,F. C. Beasley,Eoin P. Cummins,Victor Nizet,Moira K. B. Whyte,Cormac T. Taylor,Hening Lin,Seth L. Masters,Eyal Gottlieb,Vincent P. Kelly,Clary B. Clish,Philip E. Auron,Ramnik J. Xavier,Ramnik J. Xavier,Luke A. J. O'Neill +32 more
TL;DR: The authors showed that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages.
Journal ArticleDOI
Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling
Nobuhiko Kayagaki,Irma B. Stowe,Bettina L. Lee,Karen O'Rourke,Keith R. Anderson,Søren Warming,Trinna L. Cuellar,Benjamin Haley,Merone Roose-Girma,Qui T. Phung,Peter Liu,Jennie R. Lill,Hong Li,Jiansheng Wu,Sarah K. Kummerfeld,Juan Zhang,Wyne P. Lee,Scott J. Snipas,Guy S. Salvesen,Lucy X. Morris,Linda Fitzgerald,Yafei Zhang,Edward M. Bertram,Christopher C. Goodnow,Christopher C. Goodnow,Christopher C. Goodnow,Vishva M. Dixit +26 more
TL;DR: It is shown that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation and a key mediator of the host response against Gram-negative bacteria.
Journal ArticleDOI
Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores
Xing Liu,Zhibin Zhang,Zhibin Zhang,Jianbin Ruan,Jianbin Ruan,Youdong Pan,Venkat Giri Magupalli,Venkat Giri Magupalli,Hao Wu,Hao Wu,Judy Lieberman,Judy Lieberman +11 more
TL;DR: It is shown that GSDMD-NT oligomerizes in membranes to form pores that are visible by electron microscopy and kills cell-free bacteria in vitro and may have a direct bactericidal effect within the cytosol of host cells, but the importance of direct bacterial killing in controlling in vivo infection remains to be determined.
Journal ArticleDOI
Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.
Evanna L. Mills,Dylan G. Ryan,Hiran A. Prag,Dina Dikovskaya,Deepthi Menon,Zbigniew Zaslona,Mark P. Jedrychowski,Ana S. H. Costa,Maureen Higgins,Emily Hams,John Szpyt,Marah C. Runtsch,Martin S. King,Joanna F. McGouran,Roman Fischer,Benedikt M. Kessler,Anne F. McGettrick,Mark M. Hughes,Richard G. Carroll,Richard G. Carroll,Lee M. Booty,Lee M. Booty,Elena V. Knatko,Paul J. Meakin,Michael L.J. Ashford,Louise K. Modis,Gino Brunori,Daniel C. Sévin,Padraic G. Fallon,Stuart T. Caldwell,Edmund R.S. Kunji,Edward T. Chouchani,Christian Frezza,Albena T. Dinkova-Kostova,Albena T. Dinkova-Kostova,Richard C. Hartley,Michael P. Murphy,Luke A. J. O'Neill,Luke A. J. O'Neill +38 more
TL;DR: It is shown that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 by lipopolysaccharide in mouse and human macrophages and that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconates production.
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