| Structural highlights
Function
[NLRC4_MOUSE] Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis. The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria. It senses pathogenic proteins of the type III secretion system (T3SS) and type IV secretion system (T4SS) such as flagellin and PrgJ-like rod proteins via the Naip proteins (Naip1, Naip2 or Naip5): specific Naip proteins recognize and bind pathogenic proteins, driving assembly and activation of the NLRC4 inflammasome. The NLRC4 inflammasome senses Gram-negative bacteria such as L.pneumophila and P.aeruginosa, enteric pathogens S.typhimurium (Salmonella) and S.flexneri and fungal pathogen C.albicans. In intestine, the NLRC4 inflammasome is able to discriminate between commensal and pathogenic bacteria and specifically drives production of interleukin-1 beta (IL1B) in response to infection by Salmonella or P.aeruginosa. In case of L.pneumophila infection the inflammasome acts by activating caspase-7.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, like the bacterial rod protein PrgJ, and recruit the NLR family CARD-containing protein 4 (NLRC4) as the inflammasome adapter to activate innate immunity. Here we show that the PrgJ-NAIP2-NLRC4 inflammasome is assembled into multisubunit disk-like structures through a unidirectional ATPase polymerization, primed with a single PrgJ-activated NAIP2 per disk. Cryo-electron microscopy (cryo-EM) reconstruction at a subnanometer resolution revealed a ~90 degrees hinge rotation accompanying NLRC4 activation. Unlike in the related, heptameric Apaf-1 apoptosome in which each subunit needs to be conformationally activated by its ligand before assembly, a single PrgJ-activated NAIP2 initiates NLRC4 polymerization in a domino-like reaction to promote the disk assembly. These insights reveal the mechanism of signal amplification in NAIP/NLRC4 inflammasomes.
Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization.,Zhang L, Chen S, Ruan J, Wu J, Tong AB, Yin Q, Li Y, David L, Lu A, Wang WL, Marks C, Ouyang Q, Zhang X, Mao Y, Wu H Science. 2015 Oct 8. pii: aac5789. PMID:26449474[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol. 2006 Jun;7(6):569-75. Epub 2006 Apr 30. PMID:16648853 doi:10.1038/ni1344
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- ↑ Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J Exp Med. 2007 Dec 24;204(13):3235-45. Epub 2007 Dec 10. PMID:18070936 doi:10.1084/jem.20071239
- ↑ Akhter A, Gavrilin MA, Frantz L, Washington S, Ditty C, Limoli D, Day C, Sarkar A, Newland C, Butchar J, Marsh CB, Wewers MD, Tridandapani S, Kanneganti TD, Amer AO. Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection. PLoS Pathog. 2009 Apr;5(4):e1000361. doi: 10.1371/journal.ppat.1000361. Epub 2009, Apr 3. PMID:19343209 doi:10.1371/journal.ppat.1000361
- ↑ Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit VM, Monack DM. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med. 2010 Aug 2;207(8):1745-55. doi: 10.1084/jem.20100257. Epub 2010 Jul 5. PMID:20603313 doi:10.1084/jem.20100257
- ↑ Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, Warren SE, Leaf IA, Aderem A. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3076-80. doi:, 10.1073/pnas.0913087107. Epub 2010 Feb 1. PMID:20133635 doi:10.1073/pnas.0913087107
- ↑ Kofoed EM, Vance RE. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature. 2011 Aug 28;477(7366):592-5. doi: 10.1038/nature10394. PMID:21874021 doi:10.1038/nature10394
- ↑ Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, Liu L, Shao F. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature. 2011 Sep 14;477(7366):596-600. doi: 10.1038/nature10510. PMID:21918512 doi:10.1038/nature10510
- ↑ Tomalka J, Ganesan S, Azodi E, Patel K, Majmudar P, Hall BA, Fitzgerald KA, Hise AG. A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans. PLoS Pathog. 2011 Dec;7(12):e1002379. doi: 10.1371/journal.ppat.1002379. Epub, 2011 Dec 8. PMID:22174673 doi:10.1371/journal.ppat.1002379
- ↑ Cai S, Batra S, Wakamatsu N, Pacher P, Jeyaseelan S. NLRC4 inflammasome-mediated production of IL-1beta modulates mucosal immunity in the lung against gram-negative bacterial infection. J Immunol. 2012 Jun 1;188(11):5623-35. doi: 10.4049/jimmunol.1200195. Epub 2012, Apr 30. PMID:22547706 doi:10.4049/jimmunol.1200195
- ↑ Kupz A, Guarda G, Gebhardt T, Sander LE, Short KR, Diavatopoulos DA, Wijburg OL, Cao H, Waithman JC, Chen W, Fernandez-Ruiz D, Whitney PG, Heath WR, Curtiss R 3rd, Tschopp J, Strugnell RA, Bedoui S. NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8(+) T cells. Nat Immunol. 2012 Jan 8;13(2):162-9. doi: 10.1038/ni.2195. PMID:22231517 doi:10.1038/ni.2195
- ↑ Franchi L, Kamada N, Nakamura Y, Burberry A, Kuffa P, Suzuki S, Shaw MH, Kim YG, Nunez G. NLRC4-driven production of IL-1beta discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat Immunol. 2012 May;13(5):449-56. doi: 10.1038/ni.2263. PMID:22484733 doi:10.1038/ni.2263
- ↑ Qu Y, Misaghi S, Izrael-Tomasevic A, Newton K, Gilmour LL, Lamkanfi M, Louie S, Kayagaki N, Liu J, Komuves L, Cupp JE, Arnott D, Monack D, Dixit VM. Phosphorylation of NLRC4 is critical for inflammasome activation. Nature. 2012 Oct 25;490(7421):539-42. doi: 10.1038/nature11429. Epub 2012 Aug 12. PMID:22885697 doi:10.1038/nature11429
- ↑ Zhang L, Chen S, Ruan J, Wu J, Tong AB, Yin Q, Li Y, David L, Lu A, Wang WL, Marks C, Ouyang Q, Zhang X, Mao Y, Wu H. Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization. Science. 2015 Oct 8. pii: aac5789. PMID:26449474 doi:http://dx.doi.org/10.1126/science.aac5789
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