CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy

Hitoshi Tsugawa, Hideki Mori, Juntaro Matsuzaki, Akira Sato, Yoshimasa Saito, Masaya Imoto, Makoto Suematsu, Hidekazu Suzuki

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Helicobacter pylori-derived CagA, a type IV secretion system effector, plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by macroautophagy/autophagy. Hence, the induction of autophagy in H. pylori-infected epithelial cells is an important host-protective ability against gastric carcinogenesis. However, the mechanisms by which autophagosome-lysosome fusion is regulated, are unknown. Here, we report that enhancement of LAMP1 (lysosomal associated membrane protein 1) expression is necessary for autolysosome formation. LAMP1 expression is induced by nuclear translocated LRP1 (LDL receptor related protein 1) intracellular domain (LRP1-ICD) binding to the proximal LAMP1 promoter region. Nuclear translocation of LRP1-ICD is enhanced by H. pylori infection. In contrast, CAPZA1 (capping actin protein of muscle Z-line alpha subunit 1) inhibits LAMP1 expression via binding to LRP1-ICD in the nuclei. The binding of CAPZA1 to LRP1-ICD prevents LRP1-ICD binding to the LAMP1 proximal promoter. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autolysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis. Abbreviations: CagA: cytotoxin-associated gene A; CAPZA1: capping actin protein of muscle Z-line alpha subunit 1; ChIP: chromatin immunoprecipitation; GTF2I: general transcription factor IIi; HDAC: histone deacetylase; LAMP1: lysosomal associated membrane protein 1; LRP1: LDL receptor related protein 1; LRP1-ICD: CagA intracellular domain; qPCR: quantitative polymerase chain reaction; VacA: vacuolating cytotoxin.

Original languageEnglish
JournalAutophagy
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Lysosomal-Associated Membrane Protein 1
Low Density Lipoprotein Receptor-Related Protein-1
Autophagy
Helicobacter pylori
Actins
Stomach
Carcinogenesis
Muscles
Epithelial Cells
Cytotoxins
General Transcription Factors
Histone Deacetylases
plasma protein Z
Chromatin Immunoprecipitation
Helicobacter Infections
Lysosomes
Genetic Promoter Regions
Polymerase Chain Reaction

Keywords

  • Autolysosome
  • CagA
  • CAPZA1
  • gastric cancer
  • Helicobacter pylori
  • LAMP1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy. / Tsugawa, Hitoshi; Mori, Hideki; Matsuzaki, Juntaro; Sato, Akira; Saito, Yoshimasa; Imoto, Masaya; Suematsu, Makoto; Suzuki, Hidekazu.

In: Autophagy, 01.01.2018.

Research output: Contribution to journalArticle

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