What is helicobacter vac A protein?

Answer 1

vacA is a major virulating factor of h.pylori.the gm -ve bacterium produces this toxin which after entry into the host cell causes extensive vacuolation ,resulting cell death.

vac a is a 140kd protein which has a signal seq at its n terminal end (1-33 amino acid) & an autotransporter domain at c terminal (1023-1297 amino acids).after entry it breaks into 2 segments -a p33 segment & a p55 segment.these segments form a channel in the plasma membrane & helps in cell vacuolation

the mechanism of cell vacuolation by vaca is as follows:

The membranes of VacA-induced cell vacuoles contain Rab7 and other markers for late endocytic compartments

A current model for VacA-induced vacuolation proposes that VacA is internalized by cells and forms membrane channels in the membranes of late endocytic compartments .In support of this model,VacA has been found to

localize to the membranes of VacA-induced vacuoles.Intracellular expression of VacA in transiently transfected cells results in cell vacuolation

,which provides additional evidence that it can act at an intracellular site.An inhibitor of VacA channel formation, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), blocks the ability of VacA to cause cell vacuolation ,and VacA mutant toxins that lack the ability to form membrane channels also lack the ability to cause cell vacuolation, regardless of whether they are applied to the surface of cells or expressed intracellularly in transiently transfected cells

.Interestingly, a mutant toxin that lacks the ability to form membrane channels can block the activity of wild-type VacA in a dominant-negative fashion43

.This dominant-negative phenotype is associated with the formation of mixed oligomeric structures that comprise both wild-type and mutant VacA51

.The ability of a dominant-negative mutant toxin to block wild-type VacA activity provides further evidence that an oligomeric form of VacA is required for VacA cytotoxicity. Multiple cellular factors, including vacuolar ATPase,Rab7,Rac1, syntaxin 7 and dynamin, are reported to be required for VacA-induced vacuolation .These factors might be required for VacA internalization or the process of vesicle swelling.Overexpression of PIKfyve kinase has been reported to inhibit VacA-induced vacuolation,which indicates that VacA-induced cellular alterations might be related to changes in cellular phosphatidylinositol metabolism.

An important biophysical question surrounding the process of VacA-induced vacuole formation concerns the source of the membrane from which intracellular vacuoles are derived.Massive swelling of pre-existing vesicular compartments might be expected to result in lysis of these compartments if an additional source of membrane were not available.One possibility is that VacA-induced vacuoles might form as the result of fusion of multiple smaller endocytic

compartments. In support of this view, the SNARE protein syntaxin 7,which is involved in intracellular membrane fusion events, has been localized to the membranes of VacA induced vacuoles, and intracellular expression of a dominant-negative mutant form of syntaxin 7 blocks VacA-induced vacuolation

.Another possibility is that vacuoles could arise from late endosomes without a requirement for fusion of different compartments via a process involving fusion of late endosomal internal membranes with the late endosomal limiting membrane.Further studies are needed to clarify the role of membrane-fusion events in VacA-induced cell vacuolation.