| 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
Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins oligomerize into multiprotein complexes termed inflammasomes when activated. Their autoinhibition mechanism remains poorly defined. Here, we report the crystal structure of mouse NLRC4 in a closed form. The adenosine diphosphate-mediated interaction between the central nucleotide-binding domain (NBD) and the winged-helix domain (WHD) was critical for stabilizing the closed conformation of NLRC4. The helical domain HD2 repressively contacted a conserved and functionally important alpha-helix of the NBD. The C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions resulted in constitutive activation of NLRC4. Together, our data reveal the NBD-organized cooperative autoinhibition mechanism of NLRC4 and provide insight into its activation.
Crystal structure of NLRC4 reveals its autoinhibition mechanism.,Hu Z, Yan C, Liu P, Huang Z, Ma R, Zhang C, Wang R, Zhang Y, Martinon F, Miao D, Deng H, Wang J, Chang J, Chai J Science. 2013 Jul 12;341(6142):172-5. doi: 10.1126/science.1236381. Epub 2013 Jun, 13. PMID:23765277[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004 Jul 8;430(6996):213-8. Epub 2004 Jun 9. PMID:15190255 doi:10.1038/nature02664
- ↑ 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
- ↑ Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Nunez G. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol. 2006 Jun;7(6):576-82. Epub 2006 Apr 30. PMID:16648852 doi:10.1038/ni1346
- ↑ 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
- ↑ Hu Z, Yan C, Liu P, Huang Z, Ma R, Zhang C, Wang R, Zhang Y, Martinon F, Miao D, Deng H, Wang J, Chang J, Chai J. Crystal structure of NLRC4 reveals its autoinhibition mechanism. Science. 2013 Jul 12;341(6142):172-5. doi: 10.1126/science.1236381. Epub 2013 Jun, 13. PMID:23765277 doi:10.1126/science.1236381
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