Gasdermin D pore-forming activity is redox-sensitive.
CP: Immunology
Ragulator-Rag
cysteine oxidation
gasdermin D
pyroptosis
reactive oxygen species
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
31 01 2023
31 01 2023
Historique:
received:
23
04
2022
revised:
21
11
2022
accepted:
31
12
2022
pubmed:
21
1
2023
medline:
7
2
2023
entrez:
20
1
2023
Statut:
ppublish
Résumé
Reactive oxygen species (ROS) regulate the activities of inflammasomes, which are innate immune signaling organelles that induce pyroptosis. The mechanisms by which ROS control inflammasome activities are unclear and may be multifaceted. Herein, we report that the protein gasdermin D (GSDMD), which forms membrane pores upon cleavage by inflammasome-associated caspases, is a direct target of ROS. Exogenous and endogenous sources of ROS, and ROS-inducing stimuli that prime cells for pyroptosis induction, promote oligomerization of cleaved GSDMD, leading to membrane rupture and cell death. We find that ROS enhance GSDMD activities through oxidative modification of cysteine 192 (C192). Within macrophages, GSDMD mutants lacking C192 show impaired ability to form membrane pores and induce pyroptosis. Reciprocal mutagenesis studies reveal that C192 is the only cysteine within GSDMD that mediates ROS responsiveness. Cellular redox state is therefore a key determinant of GSDMD activities.
Identifiants
pubmed: 36662620
pii: S2211-1247(23)00019-0
doi: 10.1016/j.celrep.2023.112008
pmc: PMC9947919
mid: NIHMS1870539
pii:
doi:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
Inflammasomes
0
Gasdermins
0
Reactive Oxygen Species
0
Cysteine
K848JZ4886
Neoplasm Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
112008Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM142683
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI116550
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI133524
Pays : United States
Organisme : NIA NIH HHS
ID : K99 AG073461
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI167993
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.C.K. consults and holds equity in Corner Therapeutics, Larkspur Biosciences, and Neumora Therapeutics. E.T.C. is co-founder, equity holder, and board member of Matchpoint Therapeutics and co-founder and equity holder in Aevum Therapeutics. None of these relationships influenced this study.
Références
Nat Rev Mol Cell Biol. 2020 Jul;21(7):363-383
pubmed: 32231263
Free Radic Biol Med. 2016 Dec;101:93-101
pubmed: 27720842
Immunity. 2013 Aug 22;39(2):311-323
pubmed: 23954133
Cell. 2021 Aug 19;184(17):4495-4511.e19
pubmed: 34289345
Science. 2018 Nov 30;362(6418):1064-1069
pubmed: 30361383
EMBO J. 2023 Jan 4;42(1):e111389
pubmed: 36444797
Immunity. 2015 Jun 16;42(6):991-1004
pubmed: 26084020
Nature. 2015 Oct 29;526(7575):666-71
pubmed: 26375259
Nat Biotechnol. 2006 Oct;24(10):1285-92
pubmed: 16964243
Nature. 2015 Oct 29;526(7575):660-5
pubmed: 26375003
J Exp Med. 2021 Sep 6;218(9):
pubmed: 34342641
J Mol Cell Biol. 2019 Dec 19;11(12):1069-1082
pubmed: 30860577
J Biol Chem. 2002 Jun 21;277(25):22131-9
pubmed: 11940570
Blood. 2005 Oct 1;106(7):2543-50
pubmed: 15956283
Science. 2020 Sep 25;369(6511):1633-1637
pubmed: 32820063
Cell Rep. 2021 Mar 9;34(10):108756
pubmed: 33691097
Science. 2021 Jun 25;372(6549):
pubmed: 35058659
Anal Chem. 2019 Mar 19;91(6):4010-4016
pubmed: 30672687
Cell. 2010 Mar 19;140(6):821-32
pubmed: 20303873
J Immunol. 2018 May 1;200(9):3047-3052
pubmed: 29602772
Eur J Immunol. 2018 Apr;48(4):584-592
pubmed: 29274245
Nat Immunol. 2008 Aug;9(8):866-72
pubmed: 18604212
Nature. 2011 Apr 28;472(7344):476-80
pubmed: 21525932
Int J Mol Sci. 2021 Apr 28;22(9):
pubmed: 33924958
J Biol Chem. 2008 Aug 29;283(35):23510-3
pubmed: 18617526
Nature. 2021 May;593(7860):607-611
pubmed: 33883744
Anal Chem. 2014 Jul 15;86(14):7150-8
pubmed: 24927332
Nature. 2016 Jul 06;535(7610):153-8
pubmed: 27383986
Immunity. 2018 Jan 16;48(1):35-44.e6
pubmed: 29195811
Physiol Rev. 2014 Jul;94(3):909-50
pubmed: 24987008
Cell. 2010 Dec 23;143(7):1174-89
pubmed: 21183079
Cell. 2020 Mar 5;180(5):968-983.e24
pubmed: 32109415
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8103-7
pubmed: 9653147
Nature. 2012 Oct 4;490(7418):107-11
pubmed: 22902502
Proteomics. 2013 Jan;13(1):22-4
pubmed: 23148064
Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7858-63
pubmed: 27339137
Sci Immunol. 2018 Aug 24;3(26):
pubmed: 30143556
Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):17982-7
pubmed: 15604151
Nat Immunol. 2020 Jul;21(7):736-745
pubmed: 32367036
Plant Cell Environ. 2010 Apr;33(4):453-67
pubmed: 19712065
Nature. 2011 Jan 13;469(7329):221-5
pubmed: 21124315