期刊
PLOS PATHOGENS
卷 5, 期 12, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1000684
关键词
-
资金
- Deutsche Forschungsgemeinschaft [HA 2697/7-1, HA 2697/7-2, SFB576]
Translocation of the Helicobacter pylori (Hp) cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV Secretion System (T4SS) into host cells is a major risk factor for severe gastric diseases, including gastric cancer. However, the mechanism of translocation and the requirements from the host cell for that event are not well understood. The T4SS consists of inner- and outer membrane-spanning Cag protein complexes and a surface-located pilus. Previously an arginineglycine-aspartate (RGD)-dependent typical integrin/ligand type interaction of CagL with alpha 5 beta 1 integrin was reported to be essential for CagA translocation. Here we report a specific binding of the T4SS-pilus-associated components CagY and the effector protein CagA to the host cell beta 1 Integrin receptor. Surface plasmon resonance measurements revealed that CagA binding to alpha 5 beta 1 integrin is rather strong ( dissociation constant, KD of 0.15 nM), in comparison to the reported RGD-dependent integrin/fibronectin interaction (KD of 15 nM). For CagA translocation the extracellular part of the beta 1 integrin subunit is necessary, but not its cytoplasmic domain, nor downstream signalling via integrin-linked kinase. A set of beta 1 integrin-specific monoclonal antibodies directed against various defined beta 1 integrin epitopes, such as the PSI, the I-like, the EGF or the beta-tail domain, were unable to interfere with CagA translocation. However, a specific antibody (9EG7), which stabilises the open active conformation of beta 1 integrin heterodimers, efficiently blocked CagA translocation. Our data support a novel model in which the cag-T4SS exploits the beta 1 integrin receptor by an RGD-independent interaction that involves a conformational switch from the open (extended) to the closed (bent) conformation, to initiate effector protein translocation.
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