Sequence Polymorphism and Intrinsic Structural Disorder as Related to Pathobiological Performance of the Helicobacter pylori CagA Oncoprotein

Abstract

CagA, an oncogenic virulence factor produced by Helicobacter pylori, is causally associated with the development of gastrointestinal diseases such as chronic gastritis, peptic ulcers, and gastric cancer. Upon delivery into gastric epithelial cells via bacterial type IV secretion, CagA interacts with a number of host proteins through the intrinsically disordered C-terminal tail, which contains two repeatable protein-binding motifs, the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif and the CagA multimerization (CM) motif. The EPIYA motif, upon phosphorylation by host kinases, binds and deregulates Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), a bona fide oncoprotein, inducing pro-oncogenic mitogenic signaling and abnormal cell morphology. Through the CM motif, CagA inhibits the kinase activity of polarity regulator partitioning-defective 1b (PAR1b), causing junctional and polarity defects while inducing actin cytoskeletal rearrangements. The magnitude of the pathobiological action of individual CagA has been linked to the tandem repeat polymorphisms of these two binding motifs, yet the molecular mechanisms by which they affect disease outcome remain unclear. Recent studies using quantitative techniques have provided new insights into how the sequence polymorphisms in the structurally disordered C-terminal region determine the degree of pro-oncogenic action of CagA in the gastric epithelium.

Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate

“…S10 ). Whereas the hummingbird phenotype has been thought to correlate with the virulence of individual CagA 9 , 13 , 17 , 19 , little is known about the direct impact of H . pylori -delivered CagA on the stomach mucosa.…”

“…ES cell-derived organoids may therefore provide a useful tool in evaluating the relative strength of cagA -positive H . pylori virulence, which is primarily determined by the structural polymorphism of CagA 9 , 19 as well as the efficiency of CagA delivery 53 .…”

“…The CagA-PAR1b interaction inhibits PAR1b kinase activity and thereby causes junctional and polarity defects. Sequence polymorphisms in the EPIYA and CM sequences influence the binding strength of CagA with SHP2 and PAR1b 16 – 19 , respectively, which underscores the differential pathobiological activity of individual CagA that contributes to gastric carcinogenesis 19 . Indeed, oncogenic potential of H .…”

Genetic polymorphisms in the cag pathogenicity island of Helicobacter pylori and risk of stomach cancer and high‐grade premalignant gastric lesions

“…We aimed to study selected genes of the pathogenicity island cagPAI, namely cagA , cagC , cagE , cagI cagL , cagX , cagYc and cag γ. They were chosen because their functions have been well characterized in the T4SS, including CagA, 22 CagE 23 and Cagγ, 24 or because they are present extracellularly (ie, as pilus or bacterial surface‐related proteins), suggesting possible interactions with host cells, like CagC, 23,25 CagI, 26 CagL, 27 CagX 25 and CagY 28 . Variants on these genes were identified by a whole‐genome sequencing study performed on 74 Hp strains isolated from patients from Mexico and Colombia, 37 CG, 21 with IM and 16 with GC 13 .…”

Priming the seed:Helicobacter pylorialters epithelial cell invasiveness in early gastric carcinogenesis

“…The binding of CagA to PAR1b modifies this program by perturbing PAR1b localization, which translates into loss of its kinase activity, lifting of the repression of RhoA, and formation of stress fibers; the salient manifestation of this is the hummingbird phenotype[ 73 ]. The affinity of CagA for PAR1b and formation stress fibers increases proportionally to the number copies of the CagA-multimerization (CM) domain present in CagA, which is seemingly higher in East Asian CM than in Western CM and differs in five amino acid residues[ 74 ].…”