NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation.
Amino Acid Sequence
Animals
Cell Membrane
/ metabolism
Cryoelectron Microscopy
HEK293 Cells
Humans
Inflammasomes
/ metabolism
Mice
Models, Biological
Models, Molecular
Mutation
/ genetics
NIMA-Related Kinases
/ genetics
NLR Family, Pyrin Domain-Containing 3 Protein
/ chemistry
Nigericin
/ pharmacology
Protein Binding
Protein Domains
Protein Multimerization
trans-Golgi Network
/ metabolism
NEK7
NLRP3
TGN
TGN dispersion
cryo-EM
inflammasome
innate immunity
trans-Golgi network
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
22 12 2021
22 12 2021
Historique:
received:
07
09
2021
revised:
17
10
2021
accepted:
08
11
2021
pubmed:
4
12
2021
medline:
7
1
2022
entrez:
3
12
2021
Statut:
ppublish
Résumé
The NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) is emerging to be a critical intracellular inflammasome sensor of membrane integrity and a highly important clinical target against chronic inflammation. Here, we report that an endogenous, stimulus-responsive form of full-length mouse NLRP3 is a 12- to 16-mer double-ring cage held together by LRR-LRR interactions with the pyrin domains shielded within the assembly to avoid premature activation. Surprisingly, this NLRP3 form is predominantly membrane localized, which is consistent with previously noted localization of NLRP3 at various membrane organelles. Structure-guided mutagenesis reveals that trans-Golgi network dispersion into vesicles, an early event observed for many NLRP3-activating stimuli, requires the double-ring cages of NLRP3. Double-ring-defective NLRP3 mutants abolish inflammasome punctum formation, caspase-1 processing, and cell death. Thus, our data uncover a physiological NLRP3 oligomer on the membrane that is poised to sense diverse signals to induce inflammasome activation.
Identifiants
pubmed: 34861190
pii: S0092-8674(21)01326-X
doi: 10.1016/j.cell.2021.11.011
pmc: PMC8763037
mid: NIHMS1756207
pii:
doi:
Substances chimiques
Inflammasomes
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
NIMA-Related Kinases
EC 2.7.11.1
Nek7 protein, mouse
EC 2.7.11.1
Nigericin
RRU6GY95IS
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
6299-6312.e22Subventions
Organisme : NICHD NIH HHS
ID : DP1 HD087988
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI124491
Pays : United States
Organisme : NIGMS NIH HHS
ID : U24 GM129547
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests H.W. is a co-founder of Ventus Therapeutics. P.P. is a co-founder of Viva in vitro diagnostics. The other authors declare no competing interests.
Références
Science. 2017 Nov 17;358(6365):888-893
pubmed: 29146805
Nat Commun. 2018 Dec 5;9(1):5182
pubmed: 30518920
Nature. 2006 Mar 9;440(7081):237-41
pubmed: 16407889
IUCrJ. 2020 Feb 11;7(Pt 2):253-267
pubmed: 32148853
Nat Commun. 2021 May 12;12(1):2735
pubmed: 33980849
Nat Commun. 2021 Oct 6;12(1):5862
pubmed: 34615873
Cell. 2014 Mar 13;156(6):1193-1206
pubmed: 24630722
Nat Immunol. 2013 May;14(5):454-60
pubmed: 23502856
Immunity. 2018 Nov 20;49(5):842-856.e7
pubmed: 30366764
Biochem Biophys Res Commun. 2007 Aug 17;360(1):56-62
pubmed: 17586473
J Virol. 2021 Jan 13;95(3):
pubmed: 33208442
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Science. 2019 Apr 5;364(6435):
pubmed: 30948527
Arterioscler Thromb Vasc Biol. 2018 Dec;38(12):2765-2779
pubmed: 30571177
Front Immunol. 2020 Jul 08;11:1444
pubmed: 32733479
J Struct Biol. 2015 Nov;192(2):216-21
pubmed: 26278980
Nat Methods. 2017 Mar;14(3):290-296
pubmed: 28165473
Science. 2015 Oct 23;350(6259):404-9
pubmed: 26449474
Nature. 2019 Jun;570(7761):338-343
pubmed: 31189953
Nature. 2018 Dec;564(7734):71-76
pubmed: 30487600
Cell Death Differ. 2018 Jul;25(7):1194-1208
pubmed: 29765111
Nat Commun. 2017 Jun 28;8:15986
pubmed: 28656979
Cell Rep. 2014 Jan 16;6(1):196-210
pubmed: 24388751
Genes Dev. 2015 Nov 15;29(22):2349-61
pubmed: 26543158
Nat Med. 2015 Mar;21(3):248-55
pubmed: 25686105
Nature. 2006 Mar 9;440(7081):228-32
pubmed: 16407890
Curr Opin Struct Biol. 2003 Dec;13(6):665-73
pubmed: 14675543
Immunity. 2013 Jun 27;38(6):1142-53
pubmed: 23809161
IUCrJ. 2019 Jan 01;6(Pt 1):5-17
pubmed: 30713699
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
J Allergy Clin Immunol. 2021 Jun;147(6):2021-2029
pubmed: 34092352
Acta Crystallogr D Struct Biol. 2019 Oct 1;75(Pt 10):878-881
pubmed: 31588919
Nature. 2021 Aug;596(7873):583-589
pubmed: 34265844
Sci Adv. 2021 Sep 17;7(38):eabf4468
pubmed: 34524838
Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2052-2057
pubmed: 30674671
Commun Biol. 2021 Jul 15;4(1):874
pubmed: 34267316
Immunity. 2012 Sep 21;37(3):487-500
pubmed: 22981536
Curr Protoc Cell Biol. 2009 Mar;Chapter 24:Unit 24.4
pubmed: 19283730
Science. 2020 Sep 18;369(6510):
pubmed: 32943500
J Mol Biol. 2007 Sep 21;372(3):774-97
pubmed: 17681537
Nat Genet. 2001 Nov;29(3):301-5
pubmed: 11687797
Nat Chem Biol. 2019 Jun;15(6):560-564
pubmed: 31086329
Neurosci Lett. 2020 Sep 25;736:135279
pubmed: 32726591
J Struct Biol. 2005 Oct;152(1):36-51
pubmed: 16182563
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
J Exp Med. 2017 Jun 5;214(6):1725-1736
pubmed: 28465465
J Clin Invest. 2016 May 2;126(5):1783-800
pubmed: 27043286
Nat Rev Immunol. 2019 Aug;19(8):477-489
pubmed: 31036962
Cell. 2013 Apr 11;153(2):348-61
pubmed: 23582325
Nat Rev Rheumatol. 2019 Apr;15(4):190
pubmed: 30837706
Front Immunol. 2020 Aug 26;11:1828
pubmed: 32983094
Nat Immunol. 2016 Mar;17(3):250-8
pubmed: 26642356
Elife. 2018 Nov 09;7:
pubmed: 30412051
J Biol Chem. 2016 Sep 9;291(37):19487-501
pubmed: 27432880
Mol Cell. 2002 Aug;10(2):417-26
pubmed: 12191486
Elife. 2013 Sep 10;2:e01456
pubmed: 24040512
Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):1499-1504
pubmed: 29382759
J Biol Chem. 2016 Jan 1;291(1):103-9
pubmed: 26553871
Commun Biol. 2019 Jun 19;2:218
pubmed: 31240256
Nat Methods. 2017 Apr;14(4):331-332
pubmed: 28250466
Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11939-44
pubmed: 18697939
J Exp Med. 2017 Sep 4;214(9):2671-2693
pubmed: 28716882
Nature. 2011 Jan 13;469(7329):221-5
pubmed: 21124315
J Allergy Clin Immunol. 2001 Oct;108(4):615-20
pubmed: 11590390
Cell Death Dis. 2015 Oct 29;6:e1954
pubmed: 26512962
Nat Rev Immunol. 2016 Jul;16(7):407-20
pubmed: 27291964
Nat Chem Biol. 2019 Jun;15(6):556-559
pubmed: 31086327
Nature. 2016 Feb 18;530(7590):354-7
pubmed: 26814970
Immunity. 2016 Apr 19;44(4):833-46
pubmed: 27037191
Protein Sci. 2018 Jan;27(1):14-25
pubmed: 28710774
Science. 2013 Jul 12;341(6142):172-5
pubmed: 23765277
J Struct Biol. 2012 Dec;180(3):519-30
pubmed: 23000701