Helicobacter pylori infection impairs chaperone-assisted maturation of Na-K-ATPase in gastric epithelium

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2020-05, Vol.318 (5), p.G931-G945
• Main Authors: Marcus, Elizabeth A, Tokhtaeva, Elmira, Jimenez, Jossue L, Wen, Yi, Naini, Bita V, Heard, Ashley N, Kim, Samuel, Capri, Joseph, Cohn, Whitaker, Whitelegge, Julian P, Vagin, Olga
• Format: Article
• Language: English
• Subjects: Biodegradation; Cell adhesion & migration; Cell adhesion molecules; Cells, Cultured; Endoplasmic reticulum; Endoplasmic Reticulum - enzymology; Endoplasmic Reticulum - microbiology; Endoplasmic Reticulum Chaperone BiP; Enzyme Stability; Epithelial cells; Epithelial Cells - enzymology; Epithelial Cells - microbiology; Epithelium; Gastric Mucosa - enzymology; Gastric Mucosa - microbiology; Gastritis; Gastritis - enzymology; Gastritis - genetics; Gastritis - microbiology; Heat-Shock Proteins - metabolism; Helicobacter Infections - enzymology; Helicobacter Infections - genetics; Helicobacter Infections - microbiology; Helicobacter pylori; Helicobacter pylori - pathogenicity; Host-Pathogen Interactions; Humans; Immunoblotting; Infections; Mass spectroscopy; Membrane trafficking; mRNA; Mucosa; Na+/K+-exchanging ATPase; Plasma membranes; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein biosynthesis; Protein Folding; Proteolysis; Sodium; Sodium-Potassium-Exchanging ATPase - genetics; Sodium-Potassium-Exchanging ATPase - metabolism; Ubiquitin; Ubiquitination
• ISSN: 0193-1857; 1522-1547; 1522-1547
• DOI: 10.1152/ajpgi.00266.2019

infection always induces gastritis, which may progress to ulcer disease or cancer. The mechanisms underlying mucosal injury by the bacteria are incompletely understood. Here, we identify a novel pathway for -induced gastric injury, the impairment of maturation of the essential transport enzyme and cell adhesion molecule, Na-K-ATPase. Na-K-ATPase comprises α- and β-subunits that assemble in the endoplasmic reticulum (ER) before trafficking to the plasma membrane. Attachment of to gastric epithelial cells increased Na-K-ATPase ubiquitylation, decreased its surface and total levels, and impaired ion balance. did not alter degradation of plasmalemma-resident Na-K-ATPase subunits or their mRNA levels. Infection decreased association of α- and β-subunits with ER chaperone BiP and impaired assembly of α/β-heterodimers, as was revealed by quantitative mass spectrometry and immunoblotting of immunoprecipitated complexes. The total level of BiP was not altered, and the decrease in interaction with BiP was not observed for other BiP client proteins. The -induced decrease in Na-K-ATPase was prevented by BiP overexpression, stopping protein synthesis, or inhibiting proteasomal, but not lysosomal, protein degradation. The results indicate that impairs chaperone-assisted maturation of newly made Na-K-ATPase subunits in the ER independently of a generalized ER stress and induces their ubiquitylation and proteasomal degradation. The decrease in Na-K-ATPase levels is also seen in vivo in the stomachs of gerbils and chronically infected children. Further understanding of -induced Na-K-ATPase degradation will provide insights for protection against advanced disease. This work provides evidence that decreases levels of Na-K-ATPase, a vital transport enzyme, in gastric epithelia, both in acutely infected cultured cells and in chronically infected patients and animals. The bacteria interfere with BiP-assisted folding of newly-made Na-K-ATPase subunits in the endoplasmic reticulum, accelerating their ubiquitylation and proteasomal degradation and decreasing efficiency of the assembly of native enzyme. Decreased Na-K-ATPase expression contributes to -induced gastric injury.