Yes-Associated Protein Drives Helicobacter pylori–Induced Metaplastic Changes in Gastric Epithelium

BACKGROUND & AIMS: Helicobactor pylori infection triggers a spectrum of metaplastic changes in the gastric epithelium; however, the upstream regulatory mechanisms remain unclear. In human gastric epithelial models, H pylori cytotoxin-associated gene A-dependent signaling stabilized and activated yes-associated protein, thereby promoting metaplastic reprogramming of the gastric epithelium. METHODS: Human gastric tissue specimens were obtained from patients at Severance Hospital, Yonsei University College of Medicine. Human gastric epithelial cell lines (AGS, MKN74, N87, KATO III) and 8- to 10-week-old C57BL/6J mice were used. Transcriptomic analysis, immunoprecipitation, histologic and immunofluorescence staining, and molecular assays (Western blotting and quantitative reverse-transcription polymerase chain reaction) were performed to assess yes-associated protein signaling and metaplastic marker expression. RESULTS: Genetic and pharmacologic modulation of yes-associated protein and OTU deubiquitinase, ubiquitin aldehyde binding 2 demonstrated that these metaplastic marker alterations are yes-associated protein-dependent. In vivo, comparative infection with H pylori with or without cytotoxin-associated gene A revealed significantly increased spasmolytic polypeptide-expressing metaplasia markers from chief cells (Griffonia simplicifolia II lectin/gastric intrinsic factor, CD44 variant 9), parietal cell loss, and an expanded proliferative region in the presence of cytotoxin-associated gene A. Helicobacter felis infection was used to broaden the dynamic range of in vivo pathologic outcomes. Manipulating yes-associated protein specifically in chief cells with a muscle, intestine, stomach expression 1 driver verified both the induction and suppression of these lesions, and the administration of recombinant OTU deubiquitinase, ubiquitin aldehyde binding 2 and treatment with selective inhibitors enhanced and reduced metaplastic signaling, respectively. CONCLUSIONS: Yes-associated protein acts as a central regulator of H pylori-induced metaplastic transformation by reprogramming gastric epithelial and chief cell lineages. OTU deubiquitinase, ubiquitin aldehyde binding 2 serves as an upstream modulator that reinforces yes-associated protein stability and signaling, highlighting yes-associated protein as a potential therapeutic target for preventing metaplastic progression.