Structure of the Helicobacter pylori Cag Type IV Secretion System

Chung, Jeong Min; Sheedlo, M.J.; Campbell, Anne M.; Sawhney, Neha; Frick-Cheng, Arwen E; Lacy, D. Borden; Cover, Timothy L.; Ohi, Melanie D.

doi:10.1016/j.bpj.2019.11.1671

Cited by 17 publications

(30 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[52][53][54] The H. pylori T4SS is composed of additional components that are not present in the prototypical T4SSs present in other species. 53 Structural analysis by cryogenic microscopy revealed that the H. pylori T4SS contains an expanded OMCC and a symmetry mismatch between the OMCC and the PRC, 55 and its importance in CagA injection warrants further investigation. Injection of CagA requires recognition by the H. pylori T4SS of an Arg-rich CagA-secretion signal sequence (a 20-amino-acid sequence) in the carboxyl-terminal (C-terminal).…”

Section: Caga An H Pylori Virulent Protein Delivered Into Gastric Ementioning

confidence: 99%

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

2019

View full text Add to dashboard Cite

Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a "hit-and-run" process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the "hit-and-run" process of gastric carcinogenesis.

show abstract

Section: Caga An H Pylori Virulent Protein Delivered Into Gastric Ementioning

confidence: 99%

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

2019

View full text Add to dashboard Cite

show abstract

“…Eight H. pylori wild-type isolates that had been isolated from various parts of the world were included. A T4SS-deficient cagY knockout mutant (∆cagY) that can no longer express CagY, which is part of the T4SS outer membrane core complex [15], was included as control. Following infection with H. pylori for 6 h at a multiplicity of infection (MOI) of 100, the cells were investigated by phase contrast microscopy to reveal cell elongation that is the typical outcome in infected gastric AGS cells as a result of CagA's pathogenic activities.…”

Section: Oral Hn Cal-27 and Bhy Cell Lines Reveal Absence Of Cell Elmentioning

confidence: 99%

“…Colonization in the stomach depends on a number of bacterial factors, while the clinical outcome relates to presence of a chromosomally encoded pathogenicity island (PAI) carrying virulence determinants [11,12]. This so-called cagPAI is only present in highly virulent strains and encodes a type-IV secretion system (T4SS) that translocates the effector protein CagA into gastric epithelial cells [13][14][15]. Subsequently, CagA hijacks cellular signal transduction events and causes gastric AGS cells to migrate and elongate [16].…”

mentioning

confidence: 99%

Type IV secretion of Helicobacter pylori CagA into oral epithelial cells is prevented by the absence of CEACAM receptor expression

et al. 2020

View full text Add to dashboard Cite

Background: Helicobacter pylori typically colonizes the human stomach, but it can occasionally be detected in the oral cavity of infected persons. Clinical outcome as a result of gastric colonization depends on presence of the pathogenicity island cagPAI that encodes a type-IV secretion system (T4SS) for translocation of the effector protein CagA and ADP-heptose. Upon injection into target cells, CagA is phosphorylated, which can be demonstrated by in vitro infection of the gastric epithelial cell line AGS, resulting in cell elongation. Here we investigated whether H. pylori can exert these responses during interaction with cells from the oral epithelium. To this purpose, three oral epithelial cell lines, HN, CAL-27 and BHY, were infected with various virulent wild-type H. pylori strains, and CagA delivery and ADPheptose-mediated pro-inflammatory responses were monitored. Results: All three oral cell lines were resistant to elongation upon infection, despite similar bacterial binding capabilities. Moreover, T4SS-dependent CagA injection was absent. Resistance to CagA delivery was shown to be due to absence of CEACAM expression in these cell lines, while these surface molecules have recently been recognized as H. pylori T4SS receptors. Lack of CEACAM expression in HN, CAL-27 and BHY cells was overcome by genetic introduction of either CEACAM1, CEACAM5, or CEACAM6, which in each of the cell lines was proven sufficient to facilitate CagA delivery and phosphorylation upon H. pylori infection to levels similar to those observed with the gastric AGS cells. Pro-inflammatory responses, as measured by interleukin-8 ELISA, were induced to high levels in each cell line and CEACAM-independent. Conclusions: These results show that lack of CEACAM receptors on the surface of the oral epithelial cells was responsible for resistance to H. pylori CagA-dependent pathogenic activities, and confirms the important role for the T4SS-dependent interaction of these receptors with H. pylori in the gastric epithelium.

show abstract

“…Nearly 70% of all H. pylori strains isolated worldwide have been found to possess cag PAI, compared with 95% of East-Asian isolates and 60% of western isolates [ 13 , 14 ]. cag PAI is comprised of approximately 40 kb of chromosomal DNA consisting of up to 32 open reading frames (ORFs), namely cag1 to cag26 , cagA to cagZ , or cagα to cagζ , or by locus name of the HP 26,695 or HP J99 strain genomes [ 15 ] that encode effector protein CagA and components of the bacterial type IV secretion system (T4SS), which forms a syringe-like structure to deliver CagA into gastric epithelial cells [ 16 , 17 ]. However, at least 17 genes of cag PAI must be expressed to encode intact T4SS with its essential functions, and 14 genes must be expressed to fully induce interleukin-8 (IL-8) secretion [ 16 , 18 ].…”

Section: Cytotoxin-associated Gene Pathogenicity Island ( mentioning

confidence: 99%

Helicobacter pylori Virulence Factor Cytotoxin-Associated Gene A (CagA)-Mediated Gastric Pathogenicity

Ansari

Yamaoka

2020

IJMS

View full text Add to dashboard Cite

Helicobacter pylori causes persistent infection in the gastric epithelium of more than half of the world’s population, leading to the development of severe complications such as peptic ulcer diseases, gastric cancer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Several virulence factors, including cytotoxin-associated gene A (CagA), which is translocated into the gastric epithelium via the type 4 secretory system (T4SS), have been indicated to play a vital role in disease development. Although infection with strains harboring the East Asian type of CagA possessing the EPIYA-A, -B, and -D sequences has been found to potentiate cell proliferation and disease pathogenicity, the exact mechanism of CagA involvement in disease severity still remains to be elucidated. Therefore, we discuss the possible role of CagA in gastric pathogenicity.

show abstract

Structure of the Helicobacter pylori Cag Type IV Secretion System

Cited by 17 publications

References 0 publications

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

Type IV secretion of Helicobacter pylori CagA into oral epithelial cells is prevented by the absence of CEACAM receptor expression

Helicobacter pylori Virulence Factor Cytotoxin-Associated Gene A (CagA)-Mediated Gastric Pathogenicity

Contact Info

Product

Resources

About