Abstract
The type IV secretion system (T4SS) is a major virulence determinant of the gastric pathogen Helicobacter pylori. The CagL protein is a specialized adhesin of the corresponding T4SS pilus, which establishes initial contact with the integrin β1 receptor on host target cells. Recent studies proposed that Y58 and E59 amino acid polymorphisms in CagL increase the virulence of H. pylori strains by enhanced translocation and phosphorylation of the CagA effector protein. These polymorphisms were therefore correlated with an increased risk of gastric cancer development. Here we show that the Y58/E59 motif, which is located in a loop connecting two α-helices, and corresponding polymorphisms could influence the function of CagL. However, expression of isogenic CagL Y58/E59 variants in H. pylori strain 26695 significantly blocked the translocation and phosphorylation of CagA as compared to complemented wild-type CagL. These results suggest that the function of the T4SS for delivery of CagA is turned-off by the Y58/E59 mutation in CagL. This activity appears to be similar to the one recently described for another T4SS pilus protein, CagY, which is also sufficient to cause gain or loss of T4SS function. These data support the hypothesis that certain mutations in CagL or recombination events in CagY may serve as a sort of molecular switch or perhaps rheostat in the T4SS, which could alter the function of the pilus and "tunes" injection of CagA and host pro-inflammatory responses, respectively.
Highlights
In this Formal Comment we refer to the recent publication in PLOS ONE by Yeh and co-workers [1]
After the first publication by Yeh and co-workers in 2011 [3], we got interested in the potential role of CagL Y58/E59 polymorphisms in host cell interactions by the H. pylori T4SS
CagL is one of the most studied factors of the H. pylori T4SS encoded by the cag pathogenicity island (cagPAI) [15,16,17,18]
Summary
In this Formal Comment we refer to the recent publication in PLOS ONE by Yeh and co-workers [1]. This report claims that the Helicobacter pylori CagL amino acid polymorphisms Y58 and E59 increase the virulence of corresponding clinical strains. CagL is recruited to the surface of a type IV secretion system (T4SS) pilus structure, mediating contact with the integrin a5b1 receptor and translocation of the virulence factor CagA [2]. Yeh and co-workers produced H. pylori CagL mutants in one strain (Hp1033) followed by infection of AGS gastric epithelial cells and investigated the expression of integrin a5b1, CagA translocation/phosphorylation and other parameters [1]. It was claimed that H. pylori CagL Y58/E59 point mutants retain active integrin b1 with stronger binding affinity and significantly enhance CagA translocation and phosphorylation as Formal Comments are critiques of specific published articles
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