ALPK1 Controls TIFA/TRAF6-dependent Innate Immunity Against Heptose-1,7-bisphosphate of Gram-negative Bacteria

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2017 Feb 22

PMID 28222186

Citations 49

Authors

Milica Milivojevic

Anne-Sophie Dangeard

Christoph Alexander Kasper

Therese Tschon

Mario Emmenlauer

Claudine Pique

Pamela Schnupf

Julie Guignot

Cecile Arrieumerlou

Affiliations

Soon will be listed here.

Abstract

During infection by invasive bacteria, epithelial cells contribute to innate immunity via the local secretion of inflammatory cytokines. These are directly produced by infected cells or by uninfected bystanders via connexin-dependent cell-cell communication. However, the cellular pathways underlying this process remain largely unknown. Here we perform a genome-wide RNA interference screen and identify TIFA and TRAF6 as central players of Shigella flexneri and Salmonella typhimurium-induced interleukin-8 expression. We show that threonine 9 and the forkhead-associated domain of TIFA are necessary for the oligomerization of TIFA in both infected and bystander cells. Subsequently, this process triggers TRAF6 oligomerization and NF-κB activation. We demonstrate that TIFA/TRAF6-dependent cytokine expression is induced by the bacterial metabolite heptose-1,7-bisphosphate (HBP). In addition, we identify alpha-kinase 1 (ALPK1) as the critical kinase responsible for TIFA oligomerization and IL-8 expression in response to infection with S. flexneri and S. typhimurium but also to Neisseria meningitidis. Altogether, these results clearly show that ALPK1 is a master regulator of innate immunity against both invasive and extracellular gram-negative bacteria.

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References

Bernardini M, Mounier J, DHauteville H, Sansonetti P . Identification of icsA, a plasmid locus of Shigella flexneri that governs bacterial intra- and intercellular spread through interaction with F-actin. Proc Natl Acad Sci U S A. 1989; 86(10):3867-71. PMC: 287242. DOI: 10.1073/pnas.86.10.3867. View

Mahajan A, Yuan C, Lee H, Chen E, Wu P, Tsai M . Structure and function of the phosphothreonine-specific FHA domain. Sci Signal. 2008; 1(51):re12. DOI: 10.1126/scisignal.151re12. View

Murphy K, Campellone K . Lambda Red-mediated recombinogenic engineering of enterohemorrhagic and enteropathogenic E. coli. BMC Mol Biol. 2003; 4:11. PMC: 317293. DOI: 10.1186/1471-2199-4-11. View

Paciello I, Silipo A, Lembo-Fazio L, Curcuru L, Zumsteg A, Noel G . Intracellular Shigella remodels its LPS to dampen the innate immune recognition and evade inflammasome activation. Proc Natl Acad Sci U S A. 2013; 110(46):E4345-54. PMC: 3832022. DOI: 10.1073/pnas.1303641110. View

Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y . Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling. J Biol Chem. 2003; 278(14):12144-50. DOI: 10.1074/jbc.M300720200. View

Patel S, King K, Casali M, Yarmush M . DNA-triggered innate immune responses are propagated by gap junction communication. Proc Natl Acad Sci U S A. 2009; 106(31):12867-72. PMC: 2722330. DOI: 10.1073/pnas.0809292106. View

Hillier L, Graves T, Fulton R, Fulton L, Pepin K, Minx P . Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature. 2005; 434(7034):724-31. DOI: 10.1038/nature03466. View

Hasegawa M, Fujimoto Y, Lucas P, Nakano H, Fukase K, Nunez G . A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J. 2007; 27(2):373-83. PMC: 2234345. DOI: 10.1038/sj.emboj.7601962. View

Geoffroy M, Floquet S, Metais A, Nassif X, Pelicic V . Large-scale analysis of the meningococcus genome by gene disruption: resistance to complement-mediated lysis. Genome Res. 2003; 13(3):391-8. PMC: 430250. DOI: 10.1101/gr.664303. View

10.

Yin Q, Lin S, Lamothe B, Lu M, Lo Y, Hura G . E2 interaction and dimerization in the crystal structure of TRAF6. Nat Struct Mol Biol. 2009; 16(6):658-66. PMC: 2834951. DOI: 10.1038/nsmb.1605. View

11.

Dolowschiak T, Chassin C, Ben Mkaddem S, Fuchs T, Weiss S, Vandewalle A . Potentiation of epithelial innate host responses by intercellular communication. PLoS Pathog. 2010; 6(11):e1001194. PMC: 2987820. DOI: 10.1371/journal.ppat.1001194. View

12.

Sansonetti P, Arondel J, Huerre M, Harada A, Matsushima K . Interleukin-8 controls bacterial transepithelial translocation at the cost of epithelial destruction in experimental shigellosis. Infect Immun. 1999; 67(3):1471-80. PMC: 96483. DOI: 10.1128/IAI.67.3.1471-1480.1999. View

13.

Puhar A, Tronchere H, Payrastre B, Tran van Nhieu G, Sansonetti P . A Shigella effector dampens inflammation by regulating epithelial release of danger signal ATP through production of the lipid mediator PtdIns5P. Immunity. 2013; 39(6):1121-31. DOI: 10.1016/j.immuni.2013.11.013. View

14.

Schmutz C, Ahrne E, Kasper C, Tschon T, Sorg I, Dreier R . Systems-level overview of host protein phosphorylation during Shigella flexneri infection revealed by phosphoproteomics. Mol Cell Proteomics. 2013; 12(10):2952-68. PMC: 3790303. DOI: 10.1074/mcp.M113.029918. View

15.

Zhong J, Kyriakis J . Germinal center kinase is required for optimal Jun N-terminal kinase activation by Toll-like receptor agonists and is regulated by the ubiquitin proteasome system and agonist-induced, TRAF6-dependent stabilization. Mol Cell Biol. 2004; 24(20):9165-75. PMC: 517887. DOI: 10.1128/MCB.24.20.9165-9175.2004. View

16.

Sanada T, Kim M, Mimuro H, Suzuki M, Ogawa M, Oyama A . The Shigella flexneri effector OspI deamidates UBC13 to dampen the inflammatory response. Nature. 2012; 483(7391):623-6. DOI: 10.1038/nature10894. View

17.

Li H, Xu H, Zhou Y, Zhang J, Long C, Li S . The phosphothreonine lyase activity of a bacterial type III effector family. Science. 2007; 315(5814):1000-3. DOI: 10.1126/science.1138960. View

18.

Kim D, Lenzen G, Page A, Legrain P, Sansonetti P, Parsot C . The Shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes. Proc Natl Acad Sci U S A. 2005; 102(39):14046-51. PMC: 1236552. DOI: 10.1073/pnas.0504466102. View

19.

Kneidinger B, Marolda C, Graninger M, Zamyatina A, McArthur F, Kosma P . Biosynthesis pathway of ADP-L-glycero-beta-D-manno-heptose in Escherichia coli. J Bacteriol. 2001; 184(2):363-9. PMC: 139585. DOI: 10.1128/JB.184.2.363-369.2002. View

20.

Shimokata S, Oguri M, Fujimaki T, Horibe H, Kato K, Yamada Y . Association between polymorphisms of the α-kinase 1 gene and type 2 diabetes mellitus in community-dwelling individuals. Biomed Rep. 2014; 1(6):940-944. PMC: 3917034. DOI: 10.3892/br.2013.173. View