Pathogenic interactions between Helicobacter pylori adhesion protein HopQ and human cell surface adhesion molecules CEACAMs in gastric epithelial cells

Document Type: Review Article

Authors

1 Geriatrics Department, the Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China

2 Medical Record Room, the Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China

Abstract

Objective(s): The present paper aims to review the studies describing the interactions between HopQ and CEACAMs along with possible mechanisms responsible for pathogenicity of Helicobacter pylori.
Materials and Methods: The literature was searched on “PubMed” using different key words including Helicobacter pylori, CEACAM and gastric.
Results: HopQ is one of the outer membrane proteins of H. pylori and belongs to the family of adhesin proteins. In contrast to other adhesins, HopQ interacts with host cell surface molecules in a glycan independent manner. Human CEACAMs are the cell surface adhesion molecules mainly present on the epithelial cells, endothelial cells and leukocytes. The overexpression of these molecules may contribute to cancer progression and relapse. Recent studies have shown that HopQ may interact with human CEACAMs, particularly CEACAM1, CEACAM3, CEACAM5 and CEACAM6, but not CEACAM8. HopQ interacts with GFCC’C” interaction surface of IgV domain of N- terminal region of CEACAM1. Moreover, binding of HopQ to CEACAM1 prevent its trans-dimerization and stabilizes it in monomeric form. H. pylori may use these HopQ-CEACAM interactions to transfer its CagA oncoprotein into host gastric epithelial cells, which is followed by its phosphorylation and release of interleukin-8. HopQ-CEACAM interactions may also utilize T4SS, instead of CagA, to activate NF-κB signaling and trigger inflammation.
Conclusion: HopQ of H. pylori may interact with CEACAMs of the human gastric cells to induce the development of gastric ulcers and cancers by transferring CagA oncoprotein or inducing activation of T4SS to initiate and maintain inflammatory reactions.

Keywords

Main Subjects


1. Burucoa C, Axon A. Epidemiology of Helicobacter pylori infection. Helicobacter 2017; 22 Suppl 1.
2. Camilo V, Sugiyama T, Touati E. Pathogenesis of Helicobacter pylori infection. Helicobacter 2017;22Suppl 1.
3. Bugaytsova JA, Björnham O, Chernov YA, Gideonsson P, Henriksson S, Mendez M, et al. Helicobacter pylori adapts to chronic infection and gastric disease via pH-responsive BabA-mediated adherence. Cell Host Microbe 2017, 21: 376–389.
4. Karkhah A, Ebrahimpour S, Rostamtabar M, Koppolu V, Darvish S, Vasigala VKR, et al. Helicobacter pylori evasion strategies of the host innate and adaptive immune responses to survive and develop gastrointestinal diseases. Microbiol Res 2019;218:49-57.
5. Xu XC, Zhang WB, Li CX, Gao H, Pei Q, Cao BW, et al. Up-regulation of MiR-1915 inhibits proliferation, invasion, and migration of Helicobacter pylori-infected gastric cancer cells via targeting RAGE. Yonsei Med J 2019, 60:38-47.
6. Braga LLBC, Batista MHR, de Azevedo OGR, da Silva Costa KC, Gomes AD, Rocha GA, et al. oipA “on” status of Helicobacter pylori is associated with gastric cancer in North-Eastern Brazil. BMC Cancer 2019, 19:48.
7. Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of gastric cancer attributable to Helicobacter pylori. Int J Cancer 2015, 136: 487–490.
8. Yakoob J, Abbas Z, Ahmad Z, Tariq K, Awan S, Mustafa K, et al. Gastric lymphoma: association with Helicobacter pylori outer membrane protein Q (HopQ) and cytotoxic-pathogenicity activity island (CPAI) genes. Epidemiol Infect 2017;145:3468-3476.
9. Bagheri N, Shirzad H, Elahi S, Azadegan-Dehkordi F, Rahimian G, Shafigh M, et al. Downregulated regulatory T cell function is associated with increased peptic ulcer in Helicobacter pylori-infection. Microb Pathog 2017;110:165-175.
10. Matsuo Y, Kido Y, Yamaoka Y. Helicobacter pylori outer membrane protein-related pathogenesis. Toxins (Basel) 2017;9. pii: E101.
11. Chua EG, Wise MJ, Khosravi Y, Seow SW, Amoyo AA, Pettersson S, et al. Quantum changes in Helicobacter pylori gene expression accompany host-adaptation. DNA Res 2017;24:37-49.
12. Webb CT, Chandrapala D, Oslan SN, Bamert RS, Grinter RD, Dunstan RA, et al. Reductive evolution in outer membrane protein biogenesis has not compromised cell surface complexity in Helicobacter pylori. Microbiologyopen 2017; 6.
13. Zhao Q, Busch B, Jiménez-Soto LF, Ishikawa-Ankerhold H, Massberg S, Terradot L, et al. Integrin but not CEACAM receptors are dispensable for Helicobacter pylori CagA translocation. PLoS Pathog 2018;14:e1007359.
14. Ru GQ, Han Y, Wang W, Chen Y, Wang HJ, Xu WJ, et al. CEACAM6 is a prognostic biomarker and potential therapeutic target for gastric carcinoma. Oncotarget 2017;8:83673-83683.
15. Shikotra A, Choy DF, Siddiqui S, Arthur G, Nagarkar DR, Jia G, et al. A CEACAM6-high airway neutrophil phenotype and CEACAM6-high epithelial cells are features of severe asthma. J Immunol 2017;198:3307-3317.
16. Zhuo Y, Yang JY, Moremen KW, Prestegard JH. Glycosylation alters dimerization properties of a cell-surface signaling protein, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). J Biol Chem 2016;291:20085-20095.
17. Rizeq B, Zakaria Z, Ouhtit A. Towards understanding the mechanisms of actions of carcinoembryonic antigen-related cell adhesion molecule 6 in cancer progression. Cancer Sci 2018;109:33-42.
18. Han ZM, Huang HM, Sun YW. Effect of CEACAM-1 knockdown in human colorectal cancer cells. Oncol Lett 2018;16:1622-1626.
19. Xu J, Liu B, Ma S, Zhang J, Ji Y, Xu L, et al. Characterizing the tumor suppressor role of CEACAM1 in multiple myeloma. Cell Physiol Biochem 2018, 45:1631-1640.
20. Yamaguchi S, Yokoyama S, Ueno M, Hayami S, Mitani Y, Takeuchi A, et al. CEACAM1 is associated with recurrence after hepatectomy for colorectal liver metastasis. J Surg Res 2017, 220:353-362.
21. Königer V, Holsten L, Harrison U, Busch B, Loell E, Zhao Q, et al. Helicobacter pylori exploits human CEACAMs via HopQ for adherence and translocation of CagA. Nat Microbiol 2016;2:16188.
22. Javaheri A, Kruse T, Moonens K, Mejías-Luque R, Debraekeleer A, Asche CI, et al. Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs. Nat Microbiol 2016;2:16189.
23. Moonens K, Hamway Y, Neddermann M, Reschke M, Tegtmeyer N, Kruse T, et al. Helicobacter pylori adhesin HopQ disrupts trans dimerization in human CEACAMs. EMBO J. 2018 Jun 1. pii: e98665.
24. Bonsor DA, Zhao Q, Schmidinger B, Weiss E, Wang J, Deredge D, et al. The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA. EMBO J 2018 May 3. pii: e98664.
25. Coppens F, Castaldo G, Debraekeleer A, Subedi S, Moonens K, Lo A, et al. Hop-family Helicobacter outer membrane adhesins form a novel class of Type 5-like secretion proteins with an interrupted β-barrel domain. Mol Microbiol 2018,110:33-46.
26. Su YL, Huang HL, Huang BS, Chen PC, Chen CS, Wang HL, et al. Combination of OipA, BabA, and SabA as candidate biomarkers for predicting Helicobacter pylori-related gastric cancer. Sci Rep 2016;6:36442
27. Ansari S, Yamaoka Y. Helicobacter pylori BabA in adaptation for gastric colonization. World J Gastroenterol 2017;23:4158-4169.
28. Dossumbekova A, Prinz C, Mages J, Lang R, Kusters JG, Van Vliet AH, et al. Helicobacter pylori HopH (OipA) and Bacterial Pathogenicity: Genetic and Functional Genomic Analysis of hopH Gene Polymorphisms. J Infect Dis 2006, 194:1346–1355.
29. Leylabadlo HE, Yekani M, Ghotaslou R. Helicobacter pylori hopQ alleles (type I and II) in gastric cancer. Biomed Rep 2016;4:601-604.
30. Backert S, Selbach M. Role of type IV secretion in Helicobacter pylori pathogenesis. Cell Microbiol. 2008, 10:1573-1581.
31. Ohno T, Sugimoto M, Nagashima A, Ogiwara H, Vilaichone RK, Mahachai V, et al. Relationship between Helicobacter pylori hopQ genotype and clinical outcome in Asian and Western populations. J Gastroenterol Hepatol 2009, 24: 462- 468.
32. Ghavampour S, Kleefeldt F, Bömmel H, Volland J, Paus A, Horst A, et al. Endothelial barrier function is differentially regulated by CEACAM1-mediated signaling. FASEB J 2018, 32:5612-5625.
33. Klaile E, Müller MM, Schäfer MR, Clauder AK, Feer S, Heyl KA, et al. Binding of Candida albicans to Human CEACAM1 and CEACAM6 modulates the inflammatory response of intestinal epithelial cells. MBio. 2017; 8. pii: e02142-16.
34. Sintsova A, Guo CX, Sarantis H, Mak TW, Glogauer M, Gray-Owen SD. Bcl10 synergistically links CEACAM3 and TLR-dependent inflammatory signalling. Cell Microbiol 2018;20(1).
35. Schmitter T, Agerer F, Peterson L, Munzner P, Hauck CR.  Granulocyte CEACAM3 is a phagocytic receptor of the innate immune system that mediates recognition and elimination of human-specific pathogens. J Exp Med 2004, 199: 35-46.
36. Ye S, Cowled CJ, Yap CH, Stambas J. Deep sequencing of primary human lung epithelial cells challenged with H5N1 influenza virus reveals a proviral role for CEACAM1. Sci Rep 2018;8:15468.
37. Gray-Owen SD, Blumberg RS.  CEACAM1: contact-dependent control of immunity. Nat Rev Immunol 2006, 6: 433-446.
38. Löffek S, Ullrich N, Görgens A, Murke F, Eilebrecht M, Menne C, et al. CEACAM1-4L promotes anchorage-independent growth in melanoma. Front Oncol 2015, 5:234.
39. Yang C, Cao M, Liu Y, He Y, Yang C, Du Y, et al. Inhibition of cell invasion and migration by CEACAM1-4S in breast cancer. Oncol Lett 2017,14:4758-4766.
40. Müller MM, Klaile E, Vorontsova O, Singer BB, Obrink B. Homophilic adhesion and CEACAM1-S regulate dimerization of CEACAM1-L and recruitment of SHP-2 and c-Src. J Cell Biol  2009, 187: 569-581.
41. Ueshima C, Kataoka TR, Takei Y, Hirata M, Sugimoto A, Hirokawa M, et al. CEACAM1 long isoform has opposite effects on the growth of human mastocytosis and medullary thyroid carcinoma cells. Cancer Med 2017, 6:845-856.
42. Klaile E, Vorontsova O, Sigmundsson K, Müller MM, Singer BB, Ofverstedt LG, et al. The CEACAM1 N-terminal Ig domain mediates cis- and trans-binding and is essential for allosteric rearrangements of CEACAM1 microclusters. J Cell Biol 2009, 187: 553- 567.
43. Feige MH, Sokolova O, Pickenhahn A, Maubach G, Naumann M. HopQ impacts the integrin α5β1-independent NF-κB activation by Helicobacter pylori in CEACAM expressing cells. Int J Med Microbiol 2018 May 14. pii: S1438-4221(18)30094-8.
44. Schweitzer K, Sokolova O, Bozko PM, Naumann M. Helicobacter pylori induces NF-kappaB independent of CagA. EMBO Rep 2010, 11: 10–11.
45. Sokolova O, Borgmann M, Rieke C, Schweitzer K, Rothkotter HJ, Naumann M. Helicobacter pylori induces type 4 secretion system-dependent, but CagA-independent activation of IkappaBs and NF-kappaB/RelA at early time points. Int J Med Microbiol 2013, 303: 548–552.
46. Belogolova E, Bauer B, Pompaiah M, Asakura H, Brinkman V, Ertl C, et al. Helicobacter pylori outer membrane protein HopQ identified as a novel T4SS-associated virulence factor. Cell Microbiol. 2013, 15:1896-1912.
47. Yamaoka Y, Kikuchi S, El-Zimaity HMT, Gutierrez O, Osato MS, Graham DY. Importance of Helicobacter pylori oipA in clinical presentation, gastric inflammation, and mucosal interleukin 8 production. Gastroenterology 2002, 123: 414-424.
48. Yamaoka Y, Kwon DH, Graham DY. A Mr 34,000 proinflammatory outer membrane protein (OipA) of Helicobacter pylori. Proc Natl Acad Sci USA 2000, 97: 7533– 7538.