Helicobacter pylori VacA Toxin/Subunit p34: Targeting of an Anion Channel to the Inner Mitochondrial Membrane

PLoS Pathogens

Oliver Kepp¹  Michael Meinecke²  Richard Wagner²  Lars Becker²  Anke Harsman²  Grażyna Domańska³  Joachim Rassow³  Boris Reljic³  Christian Motz³  Elke A. Dian-Lothrop³  Panagiotis Papatheodorou³  Kathrin Günnewig³  Antoine Galmiche⁴ 

[1] INSERM U848, Institute Gustave Roussy, Université Paris Sud, Villejuif, France;Institut für Biophysik, Universität Osnabrück, Osnabrück, Germany;Institut für Physiologische Chemie, Ruhr-Universität Bochum, Bochum, Germany;Laboratoire de Biochimie, INSERM ERI12, Hopital Nord, CHU Amiens Picardie, Amiens, France

关键词: Mitochondria;    Outer membrane proteins;    Cell membranes;    Toxins;    Proteases;    Urea;    Membrane proteins;    Reticulocytes;   

DOI  :  10.1371/journal.ppat.1000878

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The vacuolating toxin VacA, released by Helicobacter pylori, is an important virulence factor in the pathogenesis of gastritis and gastroduodenal ulcers. VacA contains two subunits: The p58 subunit mediates entry into target cells, and the p34 subunit mediates targeting to mitochondria and is essential for toxicity. In this study we found that targeting to mitochondria is dependent on a unique signal sequence of 32 uncharged amino acid residues at the p34 N-terminus. Mitochondrial import of p34 is mediated by the import receptor Tom20 and the import channel of the outer membrane TOM complex, leading to insertion of p34 into the mitochondrial inner membrane. p34 assembles in homo-hexamers of extraordinary high stability. CD spectra of the purified protein indicate a content of >40% β-strands, similar to pore-forming β-barrel proteins. p34 forms an anion channel with a conductivity of about 12 pS in 1.5 M KCl buffer. Oligomerization and channel formation are independent both of the 32 uncharged N-terminal residues and of the p58 subunit of the toxin. The conductivity is efficiently blocked by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), a reagent known to inhibit VacA-mediated apoptosis. We conclude that p34 essentially acts as a small pore-forming toxin, targeted to the mitochondrial inner membrane by a special hydrophobic N-terminal signal.

【 授权许可】

CC BY