Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection

Autoři: Lamyaa Shaban aff001;  Giang T. Nguyen aff002;  Benjamin D. Mecsas-Faxon aff003;  Kenneth D. Swanson aff004;  Shumin Tan aff001;  Joan Mecsas aff001
Působiště autorů: Graduate Program in Molecular Microbiology, Tufts Graduate Biomedical Sciences, Boston Massachusetts, United States of America aff001;  Graduate Program in Immunology, Tufts Graduate Biomedical Sciences, Boston Massachusetts, United States of America aff002;  Dept of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston Massachusetts, United States of America aff003;  Brain Tumor Center and Neuro-Oncology Unit, Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston Massachusetts, United States of America aff004
Vyšlo v časopise: Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection. PLoS Pathog 16(5): e32767. doi:10.1371/journal.ppat.1008576
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008576


Yersinia suppress neutrophil responses by using a type 3 secretion system (T3SS) to inject 6–7 Yersinia effector proteins (Yops) effectors into their cytoplasm. YopH is a tyrosine phosphatase that causes dephosphorylation of the adaptor protein SKAP2, among other targets in neutrophils. SKAP2 functions in reactive oxygen species (ROS) production, phagocytosis, and integrin-mediated migration by neutrophils. Here we identify essential neutrophil functions targeted by YopH, and investigate how the interaction between YopH and SKAP2 influence Yersinia pseudotuberculosis (Yptb) survival in tissues. The growth defect of a ΔyopH mutant was restored in mice defective in the NADPH oxidase complex, demonstrating that YopH is critical for protecting Yptb from ROS during infection. The growth of a ΔyopH mutant was partially restored in Skap2-deficient (Skap2KO) mice compared to wild-type (WT) mice, while induction of neutropenia further enhanced the growth of the ΔyopH mutant in both WT and Skap2KO mice. YopH inhibited both ROS production and degranulation triggered via integrin receptor, G-protein coupled receptor (GPCR), and Fcγ receptor (FcγR) stimulation. SKAP2 was required for integrin receptor and GPCR-mediated ROS production, but dispensable for degranulation under all conditions tested. YopH blocked SKAP2-independent FcγR-stimulated phosphorylation of the proximal signaling proteins Syk, SLP-76, and PLCγ2, and the more distal signaling protein ERK1/2, while only ERK1/2 phosphorylation was dependent on SKAP2 following integrin receptor activation. These findings reveal that YopH prevents activation of both SKAP2-dependent and -independent neutrophilic defenses, uncouple integrin- and GPCR-dependent ROS production from FcγR responses based on their SKAP2 dependency, and show that SKAP2 is not required for degranulation.

Klíčová slova:

Fc receptors – G protein coupled receptors – Integrins – Neutrophils – Phagocytosis – Phosphorylation – Redox signaling – Spleen


1. Viboud GI, Bliska JB. Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis. Annual review of microbiology. 2005;59:69–89. doi: 10.1146/annurev.micro.59.030804.121320 15847602.

2. McNally A, Thomson NR, Reuter S, Wren BW. 'Add, stir and reduce': Yersinia spp. as model bacteria for pathogen evolution. Nat Rev Microbiol. 2016;14(3):177–90. Epub 2016/02/16. doi: 10.1038/nrmicro.2015.29 26876035.

3. Wren BW. The yersiniae—a model genus to study the rapid evolution of bacterial pathogens. Nat Rev Microbiol. 2003;1(1):55–64. doi: 10.1038/nrmicro730 15040180.

4. Cornelis GR. The type III secretion injectisome. Nat Rev Microbiol. 2006;4(11):811–25. Epub 2006/10/17. doi: 10.1038/nrmicro1526 17041629.

5. Bliska JB, Wang X, Viboud GI, Brodsky IE. Modulation of innate immune responses by Yersinia type III secretion system translocators and effectors. Cell Microbiol. 2013;15(10):1622–31. Epub 2013/07/10. doi: 10.1111/cmi.12164 23834311; PubMed Central PMCID: PMC3788085.

6. Coburn B, Sekirov I, Finlay BB. Type III secretion systems and disease. Clin Microbiol Rev. 2007;20(4):535–49. Epub 2007/10/16. doi: 10.1128/CMR.00013-07 17934073; PubMed Central PMCID: PMC2176049.

7. Green ER, Mecsas J. Bacterial Secretion Systems: An Overview. Microbiol Spectr. 2016;4(1). Epub 2016/03/22. doi: 10.1128/microbiolspec.VMBF-0012-2015 26999395; PubMed Central PMCID: PMC4804464.

8. Loeven NA, Medici NP, Bliska JB. The pyrin inflammasome in host-microbe interactions. Curr Opin Microbiol. 2020;54:77–86. Epub 2020/03/03. doi: 10.1016/j.mib.2020.01.005 32120337.

9. Peterson LW, Brodsky IE. To catch a thief: regulated RIPK1 post-translational modifications as a fail-safe system to detect and overcome pathogen subversion of immune signaling. Curr Opin Microbiol. 2020;54:111–8. Epub 2020/02/25. doi: 10.1016/j.mib.2020.01.015 32092691.

10. Sanchez-Garrido J, Slater SL, Clements A, Shenoy AR, Frankel G. Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen-host interactions. Cell Microbiol. 2020;22(4):e13184. Epub 2020/03/19. doi: 10.1111/cmi.13184 32185892.

11. Cornelis GR. Yersinia type III secretion: send in the effectors. J Cell Biol. 2002;158(3):401–8. Epub 2002/08/07. doi: 10.1083/jcb.200205077 12163464; PubMed Central PMCID: PMC2173816.

12. Davis KM, Mohammadi S, Isberg RR. Community behavior and spatial regulation within a bacterial microcolony in deep tissue sites serves to protect against host attack. Cell Host Microbe. 2015;17(1):21–31. Epub 2014/12/17. doi: 10.1016/j.chom.2014.11.008 25500192; PubMed Central PMCID: PMC4669952.

13. Crimmins GT, Mohammadi S, Green ER, Bergman MA, Isberg RR, Mecsas J. Identification of MrtAB, an ABC transporter specifically required for Yersinia pseudotuberculosis to colonize the mesenteric lymph nodes. PLoS Pathog. 2012;8(8):e1002828. Epub 2012/08/10. doi: 10.1371/journal.ppat.1002828 22876175; PubMed Central PMCID: PMC3410872.

14. Balada-Llasat JM, Mecsas J. Yersinia has a tropism for B and T cell zones of lymph nodes that is independent of the type III secretion system. PLoS Pathog. 2006;2(9):e86. Epub 2006/09/05. doi: 10.1371/journal.ppat.0020086 16948531; PubMed Central PMCID: PMC1557584.

15. Durand EA, Maldonado-Arocho FJ, Castillo C, Walsh RL, Mecsas J. The presence of professional phagocytes dictates the number of host cells targeted for Yop translocation during infection. Cell Microbiol. 2010;12(8):1064–82. doi: 10.1111/j.1462-5822.2010.01451.x 20148898; PubMed Central PMCID: PMC2906667.

16. Marketon MM, DePaolo RW, DeBord KL, Jabri B, Schneewind O. Plague bacteria target immune cells during infection. Science. 2005;309(5741):1739–41. Epub 2005/07/30. doi: 10.1126/science.1114580 16051750; PubMed Central PMCID: PMC3210820.

17. Koberle M, Klein-Gunther A, Schutz M, Fritz M, Berchtold S, Tolosa E, et al. Yersinia enterocolitica targets cells of the innate and adaptive immune system by injection of Yops in a mouse infection model. PLoS Pathog. 2009;5(8):e1000551. Epub 2009/08/15. doi: 10.1371/journal.ppat.1000551 19680448; PubMed Central PMCID: PMC2718809.

18. Isberg RR, Leong JM. Multiple beta 1 chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells. Cell. 1990;60(5):861–71. doi: 10.1016/0092-8674(90)90099-z 2311122.

19. Isberg RR, Barnes P. Subversion of integrins by enteropathogenic Yersinia. J Cell Sci. 2001;114(Pt 1):21–8. Epub 2000/12/12. 11112686.

20. Maldonado-Arocho FJ, Green C, Fisher ML, Paczosa MK, Mecsas J. Adhesins and host serum factors drive Yop translocation by yersinia into professional phagocytes during animal infection. PLoS Pathog. 2013;9(6):e1003415. Epub 2013/07/03. doi: 10.1371/journal.ppat.1003415 23818844; PubMed Central PMCID: PMC3688556.

21. Paczosa MK, Fisher ML, Maldonado-Arocho FJ, Mecsas J. Yersinia pseudotuberculosis uses Ail and YadA to circumvent neutrophils by directing Yop translocation during lung infection. Cell Microbiol. 2014;16(2):247–68. doi: 10.1111/cmi.12219 24119087; PubMed Central PMCID: PMC3981955.

22. Hoffmann R, van Erp K, Trulzsch K, Heesemann J. Transcriptional responses of murine macrophages to infection with Yersinia enterocolitica. Cell Microbiol. 2004;6(4):377–90. Epub 2004/03/11. doi: 10.1111/j.1462-5822.2004.00365.x 15009029.

23. Handley SA, Dube PH, Miller VL. Histamine signaling through the H(2) receptor in the Peyer's patch is important for controlling Yersinia enterocolitica infection. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(24):9268–73. Epub 2006/05/24. doi: 10.1073/pnas.0510414103 16717182; PubMed Central PMCID: PMC1482599.

24. Osei-Owusu P, Charlton TM, Kim HK, Missiakas D, Schneewind O. FPR1 is the plague receptor on host immune cells. Nature. 2019;574(7776):57–62. Epub 2019/09/20. doi: 10.1038/s41586-019-1570-z 31534221.

25. Sheahan KL, Isberg RR. Identification of mammalian proteins that collaborate with type III secretion system function: involvement of a chemokine receptor in supporting translocon activity. MBio. 2015;6(1):e02023–14. Epub 2015/02/19. doi: 10.1128/mBio.02023-14 25691588; PubMed Central PMCID: PMC4337563.

26. Guan KL, Dixon JE. Protein tyrosine phosphatase activity of an essential virulence determinant in Yersinia. Science. 1990;249(4968):553–6. Epub 1990/08/03. doi: 10.1126/science.2166336 2166336.

27. Zhang ZY, Clemens JC, Schubert HL, Stuckey JA, Fischer MW, Hume DM, et al. Expression, purification, and physicochemical characterization of a recombinant Yersinia protein tyrosine phosphatase. J Biol Chem. 1992;267(33):23759–66. Epub 1992/11/25. 1429715.

28. Bliska JB, Guan KL, Dixon JE, Falkow S. Tyrosine phosphate hydrolysis of host proteins by an essential Yersinia virulence determinant. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(4):1187–91. doi: 10.1073/pnas.88.4.1187 1705028; PubMed Central PMCID: PMC50982.

29. Andersson K, Carballeira N, Magnusson KE, Persson C, Stendahl O, Wolf-Watz H, et al. YopH of Yersinia pseudotuberculosis interrupts early phosphotyrosine signalling associated with phagocytosis. Molecular microbiology. 1996;20(5):1057–69. doi: 10.1111/j.1365-2958.1996.tb02546.x 8809758.

30. Logsdon LK, Mecsas J. Requirement of the Yersinia pseudotuberculosis effectors YopH and YopE in colonization and persistence in intestinal and lymph tissues. Infection and immunity. 2003;71(8):4595–607. doi: 10.1128/IAI.71.8.4595-4607.2003 12874339; PubMed Central PMCID: PMC166012.

31. Trulzsch K, Sporleder T, Igwe EI, Russmann H, Heesemann J. Contribution of the major secreted yops of Yersinia enterocolitica O:8 to pathogenicity in the mouse infection model. Infection and immunity. 2004;72(9):5227–34. Epub 2004/08/24. doi: 10.1128/IAI.72.9.5227-5234.2004 15322017; PubMed Central PMCID: PMC517446.

32. Fisher ML, Castillo C, Mecsas J. Intranasal inoculation of mice with Yersinia pseudotuberculosis causes a lethal lung infection that is dependent on Yersinia outer proteins and PhoP. Infection and immunity. 2007;75(1):429–42. Epub 2006/11/01. doi: 10.1128/IAI.01287-06 17074849; PubMed Central PMCID: PMC1828392.

33. Logsdon LK, Mecsas J. The proinflammatory response induced by wild-type Yersinia pseudotuberculosis infection inhibits survival of yop mutants in the gastrointestinal tract and Peyer's patches. Infection and immunity. 2006;74(3):1516–27. Epub 2006/02/24. doi: 10.1128/IAI.74.3.1516-1527.2006 16495522; PubMed Central PMCID: PMC1418670.

34. Di Genaro MS, Waidmann M, Kramer U, Hitziger N, Bohn E, Autenrieth IB. Attenuated Yersinia enterocolitica mutant strains exhibit differential virulence in cytokine-deficient mice: implications for the development of novel live carrier vaccines. Infection and immunity. 2003;71(4):1804–12. Epub 2003/03/26. doi: 10.1128/IAI.71.4.1804-1812.2003 12654794; PubMed Central PMCID: PMC152075.

35. Dave MN, Silva JE, Elicabe RJ, Jerez MB, Filippa VP, Gorlino CV, et al. Yersinia enterocolitica YopH-Deficient Strain Activates Neutrophil Recruitment to Peyer's Patches and Promotes Clearance of the Virulent Strain. Infection and immunity. 2016;84(11):3172–81. Epub 2016/08/24. doi: 10.1128/IAI.00568-16 27550935; PubMed Central PMCID: PMC5067750.

36. Rolan HG, Durand EA, Mecsas J. Identifying Yersinia YopH-targeted signal transduction pathways that impair neutrophil responses during in vivo murine infection. Cell Host Microbe. 2013;14(3):306–17. doi: 10.1016/j.chom.2013.08.013 24034616; PubMed Central PMCID: PMC3789382.

37. Ruckdeschel K, Roggenkamp A, Schubert S, Heesemann J. Differential contribution of Yersinia enterocolitica virulence factors to evasion of microbicidal action of neutrophils. Infection and immunity. 1996;64(3):724–33. 8641773; PubMed Central PMCID: PMC173829.

38. Andersson K, Magnusson KE, Majeed M, Stendahl O, Fallman M. Yersinia pseudotuberculosis-induced calcium signaling in neutrophils is blocked by the virulence effector YopH. Infection and immunity. 1999;67(5):2567–74. 10225922; PubMed Central PMCID: PMC116005.

39. Grosdent N, Maridonneau-Parini I, Sory MP, Cornelis GR. Role of Yops and adhesins in resistance of Yersinia enterocolitica to phagocytosis. Infection and immunity. 2002;70(8):4165–76. Epub 2002/07/16. doi: 10.1128/IAI.70.8.4165-4176.2002 12117925; PubMed Central PMCID: PMC128122.

40. Taheri N, Fahlgren A, Fallman M. Yersinia pseudotuberculosis Blocks Neutrophil Degranulation. Infection and immunity. 2016;84(12):3369–78. Epub 2016/09/14. doi: 10.1128/IAI.00760-16 27620724; PubMed Central PMCID: PMC5116715.

41. Eichelberger KR, Jones GS, Goldman WE. Inhibition of Neutrophil Primary Granule Release during Yersinia pestis Pulmonary Infection. mBio. 2019;10(6). Epub 2019/12/12. doi: 10.1128/mBio.02759-19 31822588; PubMed Central PMCID: PMC6904878.

42. Pulsifer AR, Vashishta A, Reeves SA, Wolfe JK, Palace SG, Proulx MK, et al. Redundant and Cooperative Roles for Yersinia pestis Yop Effectors in the Inhibition of Human Neutrophil Exocytic Responses Revealed by Gain-of-Function Approach. Infection and immunity. 2020;88(3). Epub 2019/12/25. doi: 10.1128/IAI.00909-19 31871100; PubMed Central PMCID: PMC7035916.

43. Moog-Lutz C, Peterson EJ, Lutz PG, Eliason S, Cave-Riant F, Singer A, et al. PRAM-1 is a novel adaptor protein regulated by retinoic acid (RA) and promyelocytic leukemia (PML)-RA receptor alpha in acute promyelocytic leukemia cells. J Biol Chem. 2001;276(25):22375–81. doi: 10.1074/jbc.M011683200 11301322.

44. Black DS, Marie-Cardine A, Schraven B, Bliska JB. The Yersinia tyrosine phosphatase YopH targets a novel adhesion-regulated signalling complex in macrophages. Cell Microbiol. 2000;2(5):401–14. Epub 2001/02/24. doi: 10.1046/j.1462-5822.2000.00061.x 11207596.

45. Marie-Cardine A, Hendricks-Taylor LR, Boerth NJ, Zhao H, Schraven B, Koretzky GA. Molecular interaction between the Fyn-associated protein SKAP55 and the SLP-76-associated phosphoprotein SLAP-130. J Biol Chem. 1998;273(40):25789–95. Epub 1998/09/25. doi: 10.1074/jbc.273.40.25789 9748251.

46. Marie-Cardine A, Verhagen AM, Eckerskorn C, Schraven B. SKAP-HOM, a novel adaptor protein homologous to the FYN-associated protein SKAP55. FEBS Lett. 1998;435(1):55–60. Epub 1998/10/02. doi: 10.1016/s0014-5793(98)01040-0 9755858.

47. Togni M, et al. Regulation of In Vitro and In Vivo Immune Functions by the Cytosolic Adaptor Protein SKAP-HOM. Molecular and cellular biology. 2005;25(18).

48. Alenghat FJ, Baca QJ, Rubin NT, Pao LI, Matozaki T, Lowell CA, et al. Macrophages require Skap2 and Sirpalpha for integrin-stimulated cytoskeletal rearrangement. J Cell Sci. 2012;125(Pt 22):5535–45. Epub 2012/09/15. doi: 10.1242/jcs.111260 22976304; PubMed Central PMCID: PMC3561861.

49. Boras M, Volmering S, Bokemeyer A, Rossaint J, Block H, Bardel B, et al. Skap2 is required for beta2 integrin-mediated neutrophil recruitment and functions. The Journal of experimental medicine. 2017;214(3):851–74. doi: 10.1084/jem.20160647 28183734; PubMed Central PMCID: PMC5339670.

50. Jordan MS, Koretzky GA. Coordination of receptor signaling in multiple hematopoietic cell lineages by the adaptor protein SLP-76. Cold Spring Harbor perspectives in biology. 2010;2(4):a002501. doi: 10.1101/cshperspect.a002501 20452948; PubMed Central PMCID: PMC2845197.

51. Clemens RA, Newbrough SA, Chung EY, Gheith S, Singer AL, Koretzky GA, et al. PRAM-1 is required for optimal integrin-dependent neutrophil function. Molecular and cellular biology. 2004;24(24):10923–32. doi: 10.1128/MCB.24.24.10923-10932.2004 15572693; PubMed Central PMCID: PMC533979.

52. Clemens RA, Lenox LE, Kambayashi T, Bezman N, Maltzman JS, Nichols KE, et al. Loss of SLP-76 expression within myeloid cells confers resistance to neutrophil-mediated tissue damage while maintaining effective bacterial killing. J Immunol. 2007;178(7):4606–14. Epub 2007/03/21. doi: 10.4049/jimmunol.178.7.4606 17372019.

53. Jakus Z, Simon E, Frommhold D, Sperandio M, Mocsai A. Critical role of phospholipase Cgamma2 in integrin and Fc receptor-mediated neutrophil functions and the effector phase of autoimmune arthritis. The Journal of experimental medicine. 2009;206(3):577–93. doi: 10.1084/jem.20081859 19273622; PubMed Central PMCID: PMC2699137.

54. Newbrough SA, Mocsai A, Clemens RA, Wu JN, Silverman MA, Singer AL, et al. SLP-76 regulates Fcgamma receptor and integrin signaling in neutrophils. Immunity. 2003;19(5):761–9. doi: 10.1016/s1074-7613(03)00305-4 14614862.

55. Nguyen GT, Green ER, Mecsas J. Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. Front Cell Infect Microbiol. 2017;7:373. Epub 2017/09/12. doi: 10.3389/fcimb.2017.00373 28890882; PubMed Central PMCID: PMC5574878.

56. Pollock JD, Williams DA, Gifford MA, Li LL, Du X, Fisherman J, et al. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet. 1995;9(2):202–9. Epub 1995/02/01. doi: 10.1038/ng0295-202 7719350.

57. Paiva CN, Bozza MT. Are reactive oxygen species always detrimental to pathogens? Antioxid Redox Signal. 2014;20(6):1000–37. Epub 2013/09/03. doi: 10.1089/ars.2013.5447 23992156; PubMed Central PMCID: PMC3924804.

58. Dupre-Crochet S, Erard M, Nubetae O. ROS production in phagocytes: why, when, and where? J Leukoc Biol. 2013;94(4):657–70. Epub 2013/04/24. doi: 10.1189/jlb.1012544 23610146.

59. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006;6(3):173–82. Epub 2006/02/25. doi: 10.1038/nri1785 16498448.

60. Mitra S, Abraham E. Participation of superoxide in neutrophil activation and cytokine production. Biochim Biophys Acta. 2006;1762(8):732–41. Epub 2006/08/22. doi: 10.1016/j.bbadis.2006.06.011 16919916.

61. Fialkow L, Wang Y, Downey GP. Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med. 2007;42(2):153–64. Epub 2006/12/27. doi: 10.1016/j.freeradbiomed.2006.09.030 17189821.

62. Harbort CJ, Soeiro-Pereira PV, von Bernuth H, Kaindl AM, Costa-Carvalho BT, Condino-Neto A, et al. Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis. Blood. 2015;126(26):2842–51. doi: 10.1182/blood-2015-05-645424 26491069; PubMed Central PMCID: PMC4692144.

63. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5. doi: 10.1126/science.1092385 15001782.

64. Keshari RS, Verma A, Barthwal MK, Dikshit M. Reactive oxygen species-induced activation of ERK and p38 MAPK mediates PMA-induced NETs release from human neutrophils. J Cell Biochem. 2013;114(3):532–40. Epub 2012/09/11. doi: 10.1002/jcb.24391 22961925.

65. Delgado-Rizo V, Martinez-Guzman MA, Iniguez-Gutierrez L, Garcia-Orozco A, Alvarado-Navarro A, Fafutis-Morris M. Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview. Front Immunol. 2017;8:81. Epub 2017/02/22. doi: 10.3389/fimmu.2017.00081 28220120; PubMed Central PMCID: PMC5292617.

66. Reeves EP, Lu H, Jacobs HL, Messina CG, Bolsover S, Gabella G, et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature. 2002;416(6878):291–7. doi: 10.1038/416291a 11907569.

67. Songsungthong W, Higgins MC, Rolan HG, Murphy JL, Mecsas J. ROS-inhibitory activity of YopE is required for full virulence of Yersinia in mice. Cell Microbiol. 2010;12(7):988–1001. doi: 10.1111/j.1462-5822.2010.01448.x 20148901; PubMed Central PMCID: PMC2897941.

68. Isberg RR. Discrimination between intracellular uptake and surface adhesion of bacterial pathogens. Science. 1991;252(5008):934–8. Epub 1991/05/17. doi: 10.1126/science.1674624 1674624.

69. Isberg RR, Tran Van Nhieu G. Binding and internalization of microorganisms by integrin receptors. Trends Microbiol. 1994;2(1):10–4. Epub 1994/01/01. doi: 10.1016/0966-842x(94)90338-7 8162429.

70. Togni M, Swanson KD, Reimann S, Kliche S, Pearce AC, Simeoni L, et al. Regulation of in vitro and in vivo immune functions by the cytosolic adaptor protein SKAP-HOM. Molecular and cellular biology. 2005;25(18):8052–63. Epub 2005/09/02. doi: 10.1128/MCB.25.18.8052-8063.2005 16135797; PubMed Central PMCID: PMC1234325.

71. Bohmer RH, Trinkle LS, Staneck JL. Dose effects of LPS on neutrophils in a whole blood flow cytometric assay of phagocytosis and oxidative burst. Cytometry. 1992;13(5):525–31. Epub 1992/01/01. doi: 10.1002/cyto.990130512 1321708.

72. Chen LY, Pan WW, Chen M, Li JD, Liu W, Chen G, et al. Synergistic induction of inflammation by bacterial products lipopolysaccharide and fMLP: an important microbial pathogenic mechanism. J Immunol. 2009;182(4):2518–24. Epub 2009/02/10. doi: 10.4049/jimmunol.0713933 19201908.

73. Mocsai A, Zhou M, Meng F, Tybulewicz VL, Lowell CA. Syk is required for integrin signaling in neutrophils. Immunity. 2002;16(4):547–58. Epub 2002/04/24. doi: 10.1016/s1074-7613(02)00303-5 11970878.

74. Graham DB, Robertson CM, Bautista J, Mascarenhas F, Diacovo MJ, Montgrain V, et al. Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCgamma2 signaling axis in mice. J Clin Invest. 2007;117(11):3445–52. Epub 2007/10/13. doi: 10.1172/JCI32729 17932569; PubMed Central PMCID: PMC2000813.

75. Futosi K, Fodor S, Mocsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. International immunopharmacology. 2013;17(3):638–50. doi: 10.1016/j.intimp.2013.06.034 23994464; PubMed Central PMCID: PMC3827506.

76. Kiefer F, Brumell J, Al-Alawi N, Latour S, Cheng A, Veillette A, et al. The Syk protein tyrosine kinase is essential for Fcgamma receptor signaling in macrophages and neutrophils. Molecular and cellular biology. 1998;18(7):4209–20. Epub 1998/06/25. doi: 10.1128/mcb.18.7.4209 9632805; PubMed Central PMCID: PMC109005.

77. El Benna J, Han J, Park JW, Schmid E, Ulevitch RJ, Babior BM. Activation of p38 in stimulated human neutrophils: phosphorylation of the oxidase component p47phox by p38 and ERK but not by JNK. Arch Biochem Biophys. 1996;334(2):395–400. Epub 1996/10/15. doi: 10.1006/abbi.1996.0470 8900416.

78. Dewas C, Fay M, Gougerot-Pocidalo MA, El-Benna J. The mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 pathway is involved in formyl-methionyl-leucyl-phenylalanine-induced p47phox phosphorylation in human neutrophils. J Immunol. 2000;165(9):5238–44. Epub 2000/10/25. doi: 10.4049/jimmunol.165.9.5238 11046057.

79. Dang PM, Morel F, Gougerot-Pocidalo MA, El Benna J. Phosphorylation of the NADPH oxidase component p67(PHOX) by ERK2 and P38MAPK: selectivity of phosphorylated sites and existence of an intramolecular regulatory domain in the tetratricopeptide-rich region. Biochemistry. 2003;42(15):4520–6. Epub 2003/04/16. doi: 10.1021/bi0205754 12693948.

80. Dang PM, Stensballe A, Boussetta T, Raad H, Dewas C, Kroviarski Y, et al. A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites. J Clin Invest. 2006;116(7):2033–43. Epub 2006/06/17. doi: 10.1172/JCI27544 16778989; PubMed Central PMCID: PMC1479423.

81. Persson C, Carballeira N, Wolf-Watz H, Fallman M. The PTPase YopH inhibits uptake of Yersinia, tyrosine phosphorylation of p130Cas and FAK, and the associated accumulation of these proteins in peripheral focal adhesions. EMBO J. 1997;16(9):2307–18. Epub 1997/05/01. doi: 10.1093/emboj/16.9.2307 9171345; PubMed Central PMCID: PMC1169832.

82. Fallman M, Andersson K, Hakansson S, Magnusson KE, Stendahl O, Wolf-Watz H. Yersinia pseudotuberculosis inhibits Fc receptor-mediated phagocytosis in J774 cells. Infection and immunity. 1995;63(8):3117–24. 7622239; PubMed Central PMCID: PMC173425.

83. Black DS, Bliska JB. Identification of p130Cas as a substrate of Yersinia YopH (Yop51), a bacterial protein tyrosine phosphatase that translocates into mammalian cells and targets focal adhesions. EMBO J. 1997;16(10):2730–44. doi: 10.1093/emboj/16.10.2730 9184219; PubMed Central PMCID: PMC1169883.

84. Black DS, Montagna LG, Zitsmann S, Bliska JB. Identification of an amino-terminal substrate-binding domain in the Yersinia tyrosine phosphatase that is required for efficient recognition of focal adhesion targets. Molecular microbiology. 1998;29(5):1263–74. doi: 10.1046/j.1365-2958.1998.01014.x 9767593.

85. Alonso A, Bottini N, Bruckner S, Rahmouni S, Williams S, Schoenberger SP, et al. Lck dephosphorylation at Tyr-394 and inhibition of T cell antigen receptor signaling by Yersinia phosphatase YopH. J Biol Chem. 2004;279(6):4922–8. doi: 10.1074/jbc.M308978200 14623872.

86. Gerke C, Falkow S, Chien YH. The adaptor molecules LAT and SLP-76 are specifically targeted by Yersinia to inhibit T cell activation. The Journal of experimental medicine. 2005;201(3):361–71. doi: 10.1084/jem.20041120 15699071; PubMed Central PMCID: PMC2213036.

87. Hamid N, Gustavsson A, Andersson K, McGee K, Persson C, Rudd CE, et al. YopH dephosphorylates Cas and Fyn-binding protein in macrophages. Microbial pathogenesis. 1999;27(4):231–42. doi: 10.1006/mpat.1999.0301 10502464.

88. Gillenius E, Urban CF. The adhesive protein invasin of Yersinia pseudotuberculosis induces neutrophil extracellular traps via beta1 integrins. Microbes Infect. 2015;17(5):327–36. Epub 2015/01/13. doi: 10.1016/j.micinf.2014.12.014 25576025.

89. Aepfelbacher M. Modulation of Rho GTPases by type III secretion system translocated effectors of Yersinia. Rev Physiol Biochem Pharmacol. 2004;152:65–77. Epub 2004/09/21. doi: 10.1007/s10254-004-0035-3 15378389.

90. Barz C, Abahji TN, Trulzsch K, Heesemann J. The Yersinia Ser/Thr protein kinase YpkA/YopO directly interacts with the small GTPases RhoA and Rac-1. FEBS Lett. 2000;482(1–2):139–43. Epub 2000/10/06. doi: 10.1016/s0014-5793(00)02045-7 11018537.

91. Navarro L, Koller A, Nordfelth R, Wolf-Watz H, Taylor S, Dixon JE. Identification of a molecular target for the Yersinia protein kinase A. Mol Cell. 2007;26(4):465–77. Epub 2007/05/29. doi: 10.1016/j.molcel.2007.04.025 17531806.

92. Trasak C, Zenner G, Vogel A, Yuksekdag G, Rost R, Haase I, et al. Yersinia protein kinase YopO is activated by a novel G-actin binding process. J Biol Chem. 2007;282(4):2268–77. Epub 2006/11/24. doi: 10.1074/jbc.M610071200 17121817.

93. Lee WL, Grimes JM, Robinson RC. Yersinia effector YopO uses actin as bait to phosphorylate proteins that regulate actin polymerization. Nat Struct Mol Biol. 2015;22(3):248–55. Epub 2015/02/11. doi: 10.1038/nsmb.2964 25664724; PubMed Central PMCID: PMC4745138.

94. Groves E, Rittinger K, Amstutz M, Berry S, Holden DW, Cornelis GR, et al. Sequestering of Rac by the Yersinia effector YopO blocks Fcgamma receptor-mediated phagocytosis. J Biol Chem. 2010;285(6):4087–98. Epub 2009/11/21. doi: 10.1074/jbc.M109.071035 19926792; PubMed Central PMCID: PMC2823549.

95. Ke Y, Tan Y, Wei N, Yang F, Yang H, Cao S, et al. Yersinia protein kinase A phosphorylates vasodilator-stimulated phosphoprotein to modify the host cytoskeleton. Cell Microbiol. 2015;17(4):473–85. Epub 2014/10/10. doi: 10.1111/cmi.12378 25298072.

96. Mohammadi S, Isberg RR. Yersinia pseudotuberculosis virulence determinants invasin, YopE, and YopT modulate RhoG activity and localization. Infection and immunity. 2009;77(11):4771–82. Epub 2009/09/02. doi: 10.1128/IAI.00850-09 19720752; PubMed Central PMCID: PMC2772528.

97. Kim C, Dinauer MC. Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways. J Immunol. 2001;166(2):1223–32. Epub 2001/01/06. doi: 10.4049/jimmunol.166.2.1223 11145705.

98. Kim C, Marchal CC, Penninger J, Dinauer MC. The hemopoietic Rho/Rac guanine nucleotide exchange factor Vav1 regulates N-formyl-methionyl-leucyl-phenylalanine-activated neutrophil functions. J Immunol. 2003;171(8):4425–30. doi: 10.4049/jimmunol.171.8.4425 14530369.

99. Yao T, Mecsas J, Healy JI, Falkow S, Chien Y. Suppression of T and B lymphocyte activation by a Yersinia pseudotuberculosis virulence factor, yopH. The Journal of experimental medicine. 1999;190(9):1343–50. Epub 1999/11/02. doi: 10.1084/jem.190.9.1343 10544205; PubMed Central PMCID: PMC2195683.

100. Condliffe AM, Webb LM, Ferguson GJ, Davidson K, Turner M, Vigorito E, et al. RhoG regulates the neutrophil NADPH oxidase. J Immunol. 2006;176(9):5314–20. Epub 2006/04/20. doi: 10.4049/jimmunol.176.9.5314 16621998.

101. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol. 2012;30:459–89. Epub 2012/01/10. doi: 10.1146/annurev-immunol-020711-074942 22224774.

102. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–75. doi: 10.1038/nri3399 23435331.

103. Ley K, Hoffman HM, Kubes P, Cassatella MA, Zychlinsky A, Hedrick CC, et al. Neutrophils: New insights and open questions. Sci Immunol. 2018;3(30). Epub 2018/12/12. doi: 10.1126/sciimmunol.aat4579 30530726.

104. Mocsai A, Zhang H, Jakus Z, Kitaura J, Kawakami T, Lowell CA. G-protein-coupled receptor signaling in Syk-deficient neutrophils and mast cells. Blood. 2003;101(10):4155–63. Epub 2003/01/18. doi: 10.1182/blood-2002-07-2346 12531806.

105. Reinhold A, Reimann S, Reinhold D, Schraven B, Togni M. Expression of SKAP-HOM in DCs is required for an optimal immune response in vivo. J Leukoc Biol. 2009;86(1):61–71. Epub 2009/04/17. doi: 10.1189/jlb.0608344 19369640.

106. Eruslanov EB, Singhal S, Albelda SM. Mouse versus Human Neutrophils in Cancer: A Major Knowledge Gap. Trends Cancer. 2017;3(2):149–60. Epub 2017/07/19. doi: 10.1016/j.trecan.2016.12.006 28718445; PubMed Central PMCID: PMC5518602.

107. Block H, Herter JM, Rossaint J, Stadtmann A, Kliche S, Lowell CA, et al. Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury. The Journal of experimental medicine. 2012;209(2):407–21. Epub 2012/02/01. doi: 10.1084/jem.20111493 22291096; PubMed Central PMCID: PMC3280874.

108. Green ER, Clark S, Crimmins GT, Mack M, Kumamoto CA, Mecsas J. Fis Is Essential for Yersinia pseudotuberculosis Virulence and Protects against Reactive Oxygen Species Produced by Phagocytic Cells during Infection. PLoS Pathog. 2016;12(9):e1005898. Epub 2016/10/01. doi: 10.1371/journal.ppat.1005898 27689357; PubMed Central PMCID: PMC5045184.

109. Dahlgren C, Karlsson A, Bylund J. Measurement of respiratory burst products generated by professional phagocytes. Methods in molecular biology. 2007;412:349–63. doi: 10.1007/978-1-59745-467-4_23 18453123.

110. Lowell CA, Fumagalli L, Berton G. Deficiency of Src family kinases p59/61hck and p58c-fgr results in defective adhesion-dependent neutrophil functions. J Cell Biol. 1996;133(4):895–910. doi: 10.1083/jcb.133.4.895 8666673; PubMed Central PMCID: PMC2120842.

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