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Infection and Immunity, December 1998, p. 6014-6016, Vol. 66, No. 12
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Identification of the Helicobacter
pylori VacA Toxin Domain Active in the Cell Cytosol
Marina
de
Bernard,1
Daniela
Burroni,2
Emanuele
Papini,1
Rino
Rappuoli,2
John
Telford,2 and
Cesare
Montecucco1,*
Centro CNR Biomembrane and Dipartimento di
Scienze Biomediche, Università di Padova, 35121 Padova1 and
Centro Ricerche IRIS,
CHIRON-Biocine Vaccines, 53100 Siena,2 Italy
Received 22 June 1998/Returned for modification 10 August
1998/Accepted 22 September 1998
 |
ABSTRACT |
Cells exposed to Helicobacter pylori toxin VacA develop
large vacuoles which originate from massive swelling of membranous compartments at late stages of the endocytic pathway. When expressed in
the cytosol, VacA induces vacuolization as it does when added from
outside. This and other evidence indicate that VacA is a toxin capable
of entering the cell cytosol, where it displays its activity. In this
study, we have used cytosolic expression to identify the portion of the
toxin molecule responsible for the vacuolating activity. VacA mutants
with deletions at the C and N termini were generated, and their
activity was analyzed upon expression in HeLa cells. We found that the
vacuolating activity of VacA resides in the amino-terminal region, the
whole of which is required for its intracellular activity.
| |
TEXT |
The vacuolating toxin VacA, produced
by pathogenic strains of Helicobacter pylori, is a major
virulence factor in the pathogenesis of gastroduodenal ulcers (4,
5, 19). Within a few hours from addition of VacA to culture
medium, cells develop intracellular vacuoles, which eventually fill the
entire cytosol and cause cell sufferance and necrosis (7,
9). Vacuoles develop in cells of the stomach mucosae of mice
(11) and dogs (17) infected orally with VacA.
Epithelial and mucosal necrosis is usually followed by cell
proliferation and tissue regeneration, but necrotic factors released
from the inflamed stomach mucosa are believed to contribute to the
establishment of chronic inflammation (18). Vacuoles are
acidic and, as such, they take up membrane-permeative weak bases such
as neutral red, which provides a rapid and quantitative assay of the
extent of vacuolization (2, 3). Vacuoles originate from late
stages of the endocytic route and contain protein markers of late
endosomes and lysosomes (12, 15, 16).
In the growth medium of H. pylori, VacA is present as a
95-kDa protein as well as 37- and 58-kDa fragments associated by
noncovalent interactions (18). Recently, it was shown that
VacA can be expressed in the cytosol of HeLa cells, where it causes the
formation of vacuoles indistinguishable from those induced by VacA
added to the medium and endocytosed by cultured cells (6,
8). Taken together, these results indicate that VacA is a toxin
capable of binding to cells and entering the cytosol, where it
expresses its toxic activity, as all A-B-type toxins do. These toxins
consist of a B domain involved in cell surface binding and in the entry in to the cell of the catalytically active A protomer (5, 6, 14). Presently, no information is available on the location of
domain A of VacA within its 95-kDa polypeptide chain and the size of
this domain.
To answer these questions, we have progressively shortened the gene
encoding VacA in such a way that smaller and smaller fragments are
produced in the cytosol of HeLa cells transfected with the vacA gene constructs. In most dichain A-B-type toxins, the A
chain is amino terminal. Thus, we began with progressive deletions at the C terminus of VacA and then analyzed the effect of N-terminal deletions. The transfected cells were assayed for vacuole formation both by visual inspection and by quantitative measurement of neutral red uptake 20 h after transfection.
The mutants with deletions at the C terminus listed in the left panel
of Fig. 1 were obtained by PCR amplification with plasmid ptox140
(10) by using appropriate 5' and 3' oligonucleotides containing SphI and BamHI restriction sites,
respectively. PCR amplifications were performed by mixing 10 ng of the
plasmid ptox140 and 50 pmol of each primer. The reaction mixtures were
preincubated for 5 min at 94°C, and 30 amplification cycles were
performed with the following scheme: denaturation at 94°C for 30 s, annealing at 50°C for 30 s, and extension at 72°C for
1.5 min. The last PCR step was performed at 72°C for 5 min. DNA
fragments were purified from agarose gels before the ligation
reaction. The vector pGEM7Zf(+) (Promega) was digested with
SphI and BamHI and mixed in a ligation reaction
with the fragments. The ligation mixture was introduced into
Escherichia coli XL-1 Blue by the CaCl2
transformation procedure. The nucleotide sequence was checked by the
dideoxy sequencing method. The N-terminus deletion mutants were
prepared by using the shortest C-terminus deletion VacA mutant
displaying full activity in the cytosol: the plasmid pGEM containing
the VacA gene from positions 316 to 2152 was digested with
SphI and EcoRI (this restriction site is
naturally present in the sequence) and ligated with the PCR products
obtained by PCR amplification with the plasmid ptox140 by using
appropriate 5' and 3' oligonucleotides containing the SphI
and EcoRI restriction sites, respectively. PCR
amplifications were performed by mixing 10 ng of the plasmid ptox140
and 50 pmol of each primer. The reaction mixtures were preincubated for
2 min at 94°C, and 27 amplification cycles were performed with the following scheme: denaturation at 94°C for 1 min, annealing at 52°C
for 2 min, and extension at 72°C for 2 min. The last PCR step was
performed at 72°C for 5 min. Plasmid DNA, prepared from ampicillin-resistant colonies, was used to transfect HeLa cells. The
transfection was performed as described before (6): briefly, HeLa cells were incubated with recombinant vaccinia virus vT7 in
Dulbecco's modified Eagle medium (DMEM) supplemented with 20 mM
HEPES (pH 7.2) for 30 min and then transfected in DMEM containing 3.7 g of NaHCO3 liter
1, 10 mM
HEPES (pH 7.2), 10 mM hydroxyurea, DNA (9 ng µl1), and
DOTAP (Boheringer) (27 ng µl1) for 2 h at 37°C.
The results obtained after this series of transfection experiments are
summarized in Fig. 1. More than 250 residues can be removed from the C terminus of the 95-kDa toxin without
any loss of vacuolating activity. Moreover, deletion of an additional
160 residues (VacA1-511) still leaves a toxin with considerable
cytosolic activity. The HeLa cells transfected with fragment 1-511 showed smaller vacuoles with a similar round appearance, mainly
localized in the perinuclear area. Similar levels of expression of
different VacA fragments (fragments 1-913, 1-511, and 1-377) were
detected, as assessed by immunoblots of transfected-cell extracts
subjected to electrophoresis and stained with anti-VacA antibodies
(data not shown). Hence, it appears that the vacuolating activity of VacA is confined to the amino-terminal portion of the polypeptide chain. The role of the residual amino-terminal part of p58, present in
the construct 1-672, which is required for activity, is most likely
that of assisting in the correct folding of the p37 domain. This
conclusion is reinforced by the analysis of the results of N-terminal
deletion, performed with the VacA1-672 construct, which is the shortest
C-terminally deleted VacA displaying full activity in the cytosol. The
N-terminally deleted VacA lacking 24 residues is totally inactive
(lower part of Fig. 1). Progressively shorter deletions were then
considered, but even the VacA6-672 construct, lacking only five
N-terminal residues, manifests a strongly reduced activity.
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FIG. 1.
Vacuolating activities of cytosol-expressed VacA
deletion mutants. The left panel lists the VacA fragments generated
inside the cytosol of HeLa cells in the present study. The right panel
reports the extent of cell vacuolation, assayed quantitatively as the
amount of neutral red taken up by transfected cells (20 h after
transfection). Data are shown as percentages of the maximal value.
Values reported are the averages for at least three different
experiments, and bars represent standard deviations. The first 33 residues, corresponding to the signal sequence, not present in the
mature toxin molecule, are not included here (4).
|
|
The results presented here show clearly that the cytosolic activity of
VacA resides in the amino-terminal region of the toxin and that its
entire N terminus is required for the induction of vacuoles by acting
in the cell cytosol. The explanation of these results is not
straightforward. The amino-terminal 24-residue-long segment has an
overall hydrophobic character (4), and it could be involved
in mediating the binding of the toxin to the cytosolic face of the cell
membrane or in directing the toxin to a selected cytosolic substrate.
Another possibility is that the removal of a few N-terminal residues
affects the stability of the protein, as was found to be the case with
human interleukin 1 beta (1). However, this does not appear
to be the case, since a control experiment performed by immunoblotting
indicated that similar levels of the different fragments are present in
the transfected cells at the time of assay of vacuolization (not shown).
It is also evident from the present work that a large portion of the
58-kDa fragment is not necessary for the cytosolic activity of VacA.
This finding is in agreement with the fact that p58 is membrane active
and increases the permeability of liposomes to K+
(13), a property shared by the B protomers of several A-B
toxins. Together, these data provide strong evidence that VacA is an
A-B-type toxin.
Using the same experimental approach, we are currently testing
the roles of different toxin segments, as well as those of single
amino acid residues of the p37 domain, even though extensive sequence comparisons run with different methods have not revealed possible biological activities of VacA, which could pinpoint selected residues to be mutagenized. Such information will be highly valuable in
the design of VacA mutants to be considered as possible components of a
therapeutic vaccine against the gastroduodenal diseases caused by
H. pylori.
| |
ACKNOWLEDGMENTS |
We thank Stefano Censini for the synthesis of oligonucleotides and
for gene sequencing.
This work was supported by grants from the European Community (TMR FMRX
CT96 0004 and Biomed-2 BMH4 CT97 2410), from the Armenise-Harvard Medical School Foundation, and from CNR Progetto Finalizzato
Biotecnologie (97.01168.PF 49) and has been carried out in part under a
research contract with Consorzio Autoimmunità Tardiva C.A.U.T.,
Pomezia, Italy, within the "Programma Nazionale Farmaci-seconda
fase" of the Italian Ministry of the University Scientific and
Technological Research.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Centro CNR
Biomembrane and Dipartimento di Scienze Biomediche, Università di
Padova, Via G. Colombo 3, 35121 Padva, Italy. Phone: 39-49-8276058. Fax: 39-49-8276049. E-mail: cesare{at}civ.bio.unipd.it.
Editor:
J. T. Barbieri
| |
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Infection and Immunity, December 1998, p. 6014-6016, Vol. 66, No. 12
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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