- The Helicobacter pylori CagA protein is a multifunctional effector injected into host gastric epithelial cells via the type IV secretion system. While much attention has focused on its phosphorylation-dependent interactions—particularly with SHP-2 tyrosine phosphatase—CagA also exerts potent effects independently of phosphorylation.
- One of the best-characterized phosphorylation-independent mechanisms involves direct interaction with the polarity-regulating kinase PAR1b (also known as MARK2), a key player in maintaining apical–basal polarity in epithelial tissues.
- PAR1b is a serine/threonine kinase that orchestrates epithelial polarity by stabilizing the microtubule network and phosphorylating substrates such as MAP2, MAP4, and Tau. Through these actions, it ensures the segregation of membrane domains and the maintenance of a defined apical–basolateral axis.
- CagA disrupts this regulatory function by binding to PAR1b through a conserved CagA multimerization (CM) motif. This interaction does not require CagA phosphorylation and occurs independently of the EPIYA motifs. The CM motif docks directly onto the kinase domain of PAR1b, acting as a pseudosubstrate that blocks its kinase activity.
- The inhibition of PAR1b by CagA leads to profound consequences for epithelial cell architecture. With PAR1b activity suppressed, the microtubule cytoskeleton becomes disorganized, and polarity complexes such as Par3–Par6–aPKC lose their spatial confinement. This disruption leads to the loss of apical–basal polarity, cell spreading, and a breakdown in the ordered arrangement of epithelial monolayers.
- Although this polarity loss alone does not fully account for the dramatic “hummingbird phenotype” observed in AGS cells—which requires additional CagA phosphorylation and SHP-2 activation—it is a critical early step in weakening epithelial integrity and promoting cellular disarray.
- Importantly, the CagA–PAR1b interaction appears to be highly specific. Mutations in the CM motif abolish PAR1b binding and prevent polarity disruption, without affecting CagA’s other signaling interactions. This makes the CM motif a promising therapeutic target.
- Blocking the CagA–PAR1b interaction could preserve epithelial polarity and resist the early epithelial remodeling that primes tissues for inflammation, hyperplasia, or oncogenic transformation.
- In summary, the CagA–PAR1b interaction represents a central, phosphorylation-independent pathway by which H. pylori compromises gastric epithelial cell polarity. By directly inhibiting a key polarity kinase, CagA undermines the structural and signaling framework of the epithelium, creating a permissive environment for further pathogenesis. Understanding and targeting this interaction may offer new avenues for preventing H. pylori-induced gastric disease.
