Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein.
When delivered into gastric epithelial cells via type IV secretion, Helicobacter pylori CagA perturbs host cell signaling and thereby promotes gastric carcinogenesis. However, the mechanisms of CagA delivery, localization, and action remain poorly understood. We show that direct contact of H. pylori with epithelial cells induces externalization of the inner leaflet enriched host phospholipid, phosphatidylserine, to the outer leaflet of the host plasma membrane. CagA, which is exposed on the bacterial surface via type IV secretion, interacts with the externalized phosphatidylserine to initiate its entry into cells. CagA delivery also requires energy-dependent host cell processes distinct from known endocytic pathways. Within polarized epithelial cells, CagA is tethered to the inner leaflet of the plasma membrane through interaction with phosphatidylserine and binds the polarity-regulating host kinase PAR1/MARK to induce junctional and polarity defects. Thus, host membrane phosphatidylserine plays a key role in the delivery, localization, and pathophysiological action of CagA.
Murata-Kamiya
Naoko
N
Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Kikuchi
Kenji
K
Hayashi
Takeru
T
Higashi
Hideaki
H
Hatakeyama
Masanori
M
D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004285:Dogs; D004847:Epithelial Cells / Q000382:microbiology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D015513:Oncogene Proteins / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism*; D021381:Protein Transport; D037521:Virulence Factors / Q000378:metabolism*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D015513:Oncogene Proteins; D010718:Phosphatidylserines; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori