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Cutting Edge |
B Pathway1
* Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109; and
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B transcription factor and
augments apoptosis in human epithelial cells. This activity is
similar but mechanistically distinct from that described for YopJ, an
AvrA homolog expressed by the bacterial pathogen
Yersinia. We suggest that AvrA may limit virulence in
vertebrates in a manner analogous to avirulence factors in plants, and
as such, is the first bacterial effector from a mammalian pathogen that
has been ascribed such a function. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B pathway when stimulated by multiple proinflammatory agonists,
including virulent S. typhimurium (2). These
effects were mediated by a block in IB-
ubiquitination while
IB- phosphorylation was unaffected.
Recently, a family of secreted bacterial proteins has been implicated
in the establishment of parasitic, commensal, and symbiotic
prokaryotic-eukaryotic interactions (3, 4). These proteins
share sequence and structural homology with the cysteine proteases from
adenovirus and the ubiquitin-like protein proteases from eukaryotes.
One example is the Yersinia effector YopJ that has been
shown to block the innate immune response in infected mammalian cells
(macrophages) (5). YopJ inhibits the activation of
mitogen-activated protein kinase
(MAPK)3 kinases and
the IB kinases (IKK), resulting in inhibition of MAPK and
NF-B signaling pathways (6). Intriguingly, the AvrBsT
homolog found in phytopathogenic Xanthomonas campestris
mediates an "avirulence" function. Specifically, expression of
AvrBsT in infected plant cells elicits a host defense
(hypersensitivity) response that results in local apoptosis of
infected cells and serves to limit further infection by the invading
organism (7). Finally, a homolog, Y4LO, from
Rhizobia sp. may be instrumental in the establishment of a
long-term symbiotic state by modulating, rather than disrupting, host
defense responses in the root nodule cells of leguminous plants
(8).
AvrA, a member of the YopJ/Avr family of proteins (3),
exists in most Salmonella, however previous studies did not
establish a role for this protein (9, 10). Based on our
previous observations with NF-B-inhibitory Salmonella, we
hypothesized that AvrA was the effector responsible for the observed
inhibition of NF-B signaling.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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S. typhimurium PhoPc (1), SL3201, and S. pullorum were cultured and used to colonize epithelial cells as previously described (2). Salmonella strains carrying a nonpolar mutation in avrA were constructed by ligation of a 2 kbp EcoRV fragment from pUI1637 (11) conferring resistance to kanamycin into the unique BstBI site of avrA after a fill-in reaction with Klenow. The disrupted allele was introduced into the Salmonella chromosome by homologous recombination using the pGP704 suicide plasmid (12). The chromosomal configuration of kanamycin-resistant strains was confirmed by Southern hybridization analyses using a nonisotopic detection kit (Roche, Indianapolis, IN) with an avrA probe. avrA appears to be encoded as a single transcriptional unit, and thus, disruption should not have polar effects on the expression of downstream genes (10).
Transient transfections and reporter assays
HeLa cells (40–60% confluent) were transiently transfected
using Superfect reagent (Qiagen, Valencia, CA) according to the
manufacturer’s instructions and were allowed 16–24 h for expression.
DNA quantities were as follows: for chloramphenicol acetyl transferase
(CAT) reporter assay, 2 µg pIL-8-CAT, 0–100 ng vector
(pCMV-myc or pSFFV) and/or expression plasmid per well in a
6-well plate; for immunofluorescence studies, 0.5 µg
pCMV-myc-AvrA or AvrAC186A per 12-mm coverslip; for Western
blot, 2 µg each pIB--FLAG and pCMV5-
MAPK/extracellular
signal-regulated kinase kinase kinase (MEKK)1-HA, 250 ng each
AvrA, YopJ, AvrA/C186A, YopJ/C172A expression plasmids. Transfections
of 293 cells were performed as previously described (6).
DNA quantities were as follows: 40 ng pNF-B-Luc (Stratagene, La
Jolla, CA), 25 ng pcDNA-p65, 50 ng pCMV5-MEKK1-HA, 400 ng
pcDNA-IKK-
, and 20, 100, and 40 ng of pCMV-myc-AvrA or
pSFFV-YopJ-Flag with p65, MEKK or IKK, respectively.
pCMV-lacZ (200 ng) was included in some experiments to
normalize results for transfection efficiency. CAT (13),
luciferase, and -galactosidase activities (6) were
measured as described previously.
Immunofluorescence studies
Immunofluorescent labeling of transiently transfected adherent HeLa cells grown on 12-mm glass coverslips was performed as follows: cells were fixed for 20 min in 3.7% paraformaldehyde in PBS, washed in PBS, permeabilized with 0.1% Triton X-100 in PBS for 5 min, and washed again. Fixed samples were incubated in blocking solution (5% normal goat serum in PBS) overnight at 4°C. A 1-hr incubation with each Ab diluted in blocking buffer followed: 1/500 rabbit anti-p65 (Rockland, Gilbertsville, PA); 1/200 fluorescein (FITC)-conjugated goat anti-rabbit IgG (Jackson ImmunoResearch Laboratories, West Grove, PA); 1/300 c-Myc monoclonal (Clontech Laboratories, Palo Alto, CA); 1/300 rhodamine (tetramethylrhodamineisothiocyanate)-conjugated goat anti-mouse IgG (Jackson ImmunoResearch Laboratories). Cells were washed three times between each Ab. The coverslips were mounted on glass slides and stained cells were observed by laser confocal epifluorescence microscopy (Zeiss, Oberkochen, Germany).
Western blot analysis
Cell lysates were prepared, electrophoresed on
SDS-polyacrylamide gels, and transferred to nitrocellulose as
previously described (2). Immunoreactive proteins were
detected with Abs to IB- (Santa Cruz Biotechnology, Santa Cruz,
CA), phospho-IB- (Cell Signaling Technology, Beverly, MA),
MEKK1 (Santa Cruz Biotechnology), or c-myc (Clontech
Laboratories) using ECL (Amersham, Piscataway, NJ) and a HRP-conjugated
donkey anti-rabbit secondary Ab. Blots were exposed to film for
1–5 min.
Apoptosis assays
After 18–24 h of treatment, 1 x 106 adherent HeLa cells were trypsinized and incubated with FITC-conjugated annexin V (binds to phosphatidyl serine on the cytoplasmic surface of the cell membrane) and propidium iodide (PI) for 15 min in the dark according to the manufacturer’s protocol (Annexin VFITC Apoptosis Detection kit; Oncogene Research Products, San Diego, CA). Cells were analyzed by flow cytometry.
Real-time quantitative RT-PCR (qRT-PCR) analysis of IL-8 mRNA
Total RNA was extracted from treated HT-29 cells using TRIzol reagent and reverse-transcribed using a commercial kit (TaqMan Reverse Transcription (RT) kit; PerkinElmer, Boston, MA) according the manufacturer’s directions. The RT cDNA reaction products were subjected to real-time quantitative PCR (SYBR Green PCR Core kit; PerkinElmer) with primers for IL-8 (Invitrogen, Carlsbad, CA) and 18s ribosomal RNA (PerkinElmer) as previously described (14). The IL-8 expression level was normalized to the 18s rRNA level of the same sample. Fold difference was the ratio of the normalized value of each sample to that of uninfected control cells. All PCR were performed in triplicate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-induced activation of a NF-B-dependent IL-8-CAT reporter in
a dose-dependent fashion (Fig. 1
a). Expression of a mutant
AvrA protein with a single amino acid residue transition (AvrA/C186A)
in a putative catalytic cysteine of this enzyme did not prevent
TNF--stimulated induction of the reporter. Similarly, the
corresponding catalytically inactivated mutant YopJ/C172A
(15) had no effect, while wild-type YopJ mediated a
repressive effect similar to that of wild-type AvrA (Fig. 1b).
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B
to study activation of this signaling pathway. As previously shown,
TNF- induces cytoplasmic to nuclear translocation of p65
(2) (Fig. 1
c). However, expression of
AvrA-myc in HeLa epithelial cells prevented the nuclear
translocation of p65 in response to TNF- (Fig. 1c,
arrowheads), while mutant AvrA/C186A did not block p65 translocation.
Collectively, these results indicate that AvrA is sufficient to inhibit
the NF-B pathway, presumably by an enzymatic activity similar to
that of homologous ubiquitin-like protein proteases in other animal and
plant pathogens (15).
To identify the point of disruption of the NF-B pathway by AvrA, we
performed a biochemical epistasis assay. 293 cells were transfected
with a NF-B-dependent reporter gene plasmid and plasmids for
expression of p65, IKK-, or an activated form of MEKK1, and AvrA or
YopJ. In this assay, MEKK1, IKK-, and p65 were used to activate
gene transcription via the NF-B pathway and the effects of
equivalent amounts of AvrA and YopJ were assessed. Neither AvrA nor
YopJ inhibited expression of the reporter gene when stimulated by p65
(Fig. 2a), indicating that
inhibition of the NF-B pathway mediated by both AvrA and YopJ occurs
at a step that is proximal to p65 nuclear translocation and
transcriptional activation. In contrast, both AvrA and YopJ inhibited
expression of the reporter gene when stimulated by MEKK1, the MAPK
kinase kinase responsible for phosphorylation of IKK
(Fig. 2b). Finally, when cells were stimulated by the
physiologic, proinflammatory IKK-, AvrA inhibited reporter gene
expression while YopJ had little effect (Fig. 2c). Thus,
AvrA blocks the NF-B pathway downstream of IKK activation while YopJ
blocks at a point upstream of IKK activation (Fig. 2d).
These data show that although these two molecules are 86% similar in
amino acid sequence, they are working, mechanistically, in distinct
manners to block NF-B signaling.
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B- phosphorylation. HeLa cells were
transfected with plasmids expressing IB--FLAG, MEKK1 (as the
activator of endogenous IKK), and wild-type or mutant AvrA or YopJ.
Strikingly, Western blotting of cell lysates revealed that while
expression of AvrA had relatively little effect on
phosphorylation of IB-, expression of wild-type
YopJ prevented the appearance of phospho-IB- (Fig. 2e). This data is consistent with our previous observation
that NF-B-inhibitory Salmonella do not block IB-
phosphorylation in colonized epithelial cells
(2). It also correlates with a previous result that YopJ
blocks the activation of the superfamily of MAPK kinases
(6) and the above observation that AvrA is working distal
to this point.
Endogenous and exogenous inhibitors of the NF-B pathway are potently
proapoptotic (16). AvrA null mutants were constructed by
disrupting the chromosomal avrA gene in strains of
Salmonella that exhibited the NF-B inhibitory phenotype,
S. typhimurium PhoPc or S.
pullorum, and were analyzed for the ability to modulate epithelial
apoptotic and proinflammatory pathways. Colonization of HeLa epithelial
cells for extended periods by PhoPc or S.
pullorum strains initiated apoptosis in 9–16% of the
total intact cell population as measured by flow cytometry of annexin
V- and PI-stained cells (Fig. 3, a and e). In contrast, basal levels of
apoptosis similar to an uninfected control (3–6% of intact
population) are observed when cells are colonized by the AvrA null
mutants under the same conditions (Fig. 3, b, f,
d, and h). In a complementation experiment,
colonization by AvrA null strains expressing AvrA from a plasmid in
trans induced levels of apoptosis (13–17% of
cells) that were equal to or greater than that observed with
PhoPc or S. pullorum (Fig. 3, c and g).
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B-inhibitory and -derived AvrA
mutant strains on direct proinflammatory signaling events such as IL-8
expression. HeLa cells were transiently transfected with a
NF-B-dependent IL-8 promoter-CAT reporter plasmid and CAT expression
was measured in colonized cells. As previously shown, TNF- induces
significant CAT expression, but colonization with S.
pullorum represses 
90% of this activation (Fig. 4a) (2). The
S. pullorum AvrA mutant repressed only 55% of
TNF--stimulated CAT expression and, therefore, has partially lost
the ability to block proinflammatory signaling. In addition, IL-8
expression levels are higher in HT-29 epithelial cells colonized with
AvrA mutant strains than in cells colonized with the parent inhibitory
strains PhoPc or S. pullorum (Fig. 4b) as demonstrated by real-time qRT-PCR. Together, these
data reveal that AvrA is a significant contributor in the observed
inhibition of proinflammatory signaling by NF-B-inhibitory
Salmonella strains.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B pathway in cultured human epithelia and results in consequent
activation of apoptosis. Our data indicates that AvrA and YopJ,
two similar molecules presumably involved in the metabolism of
ubiquitin or related molecules, have evolved to inhibit the NF-B
pathway at separate points. As we have shown, YopJ is a potent
inhibitor of IB- phosphorylation in vivo and in
vitro (6), while AvrA is not, indicating different points
of action. This observation underscores the crucial, multifaceted role
that modification by ubiquitin-like molecules plays in the NF-B
pathway, and perhaps in other stress-induced signaling pathways. At
least two ubiquitin modification events are critical in the activation
of the NF-B pathway: the typical Lys48-linked
polyubiquitination of IB necessary for proteasomal degradation
(17), and the Lys63-linked ubiquitination of
TNFR-associated factor 6 necessary for IKK catalytic activation
(18). Furthermore, modification of the Cul subunit of the
Skp1/Cul/F-box ubiquitin ligase complex by the ubiquitin-like
molecule Nedd-8 has been shown to be necessary for IB degradation
(19). Neither recombinant AvrA nor YopJ are able to
hydrolyze in vitro ubiquitinated IB- (data not shown), suggesting
that these proteins do not directly deubiquitinate IB-. It is
possible that YopJ inhibits proximal events such as TNFR-associated
factor 6 modification, while AvrA may influence a more distal event,
such as Skp1/Cul/F-box ubiquitin ligase activation.
Bacterial effectors of the ubiquitin-like protein protease family are
believed to exert their function by initiating or augmenting
apoptosis, presumably by inhibition of NF-B or related
anti-apoptotic pathways (3). In certain
Salmonella infections, the presence of AvrA in the infected
epithelia would result in accelerated apoptosis, allowing
elimination of the infected cells and prevention of systemic spread. As
epithelial cells are rapidly replaced, having a crypt-to-villus life
span of 3–5 days (20), apoptosis-mediated cell
death would not have deleterious systemic consequences (as would be the
case with loss of macrophages). Significantly, Salmonella
typhi and paratyphi are strains that evade epithelial
defenses and result in severe systemic disease (within macrophages).
These strains invariably do not possess an avrA allele
(21). Consistently, Grassme et al. (22)
reported that in vivo murine airway infection by Pseudomonas
aeruginosa results in apoptosis of respiratory epithelial
cells and limitation of further infection. In contrast, respiratory
infection in mice genetically deficient in the CD95/CD95-ligand
apoptotic activation pathway results in systemic dissemination of the
airway pathogen and rapid death. The observations described in this
study support the hypothesis that the mammalian host may exploit
apoptosis of rapidly turned over epithelial cell types as a
defense mechanism. This strategy is functionally analogous to the
interaction of plant pathogen Avr homologs with the R genes of
resistant plants (23) in that the recognition of infection
causes induction of the host defense response. These observations shed
new light on mechanisms of pathogenic, commensal, and even symbiotic
relationships between a eukaryotic host and associated prokaryotes.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Andrew S. Neish, Department of Pathology, Emory University School of Medicine, Whitehead Building, Room 105F, 615 Michael Street, Atlanta GA, 30322. E-mail address: aneish{at}emory.edu
3 Abbreviations used in this paper: MAPK, mitogen-activated protein kinase; IKK, I-B kinase; CAT, chloramphenicol acetyl transferase; MEKK, MAPK/extracellular signal-regulated kinase kinase kinase; PI, propidium iodide; RT, reverse transcription; qRT-PCR, quantitative RT-PCR.
Received for publication June 11, 2002. Accepted for publication July 30, 2002.
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References |
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B- ubiquitination. Science 289:1560.B antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:1680.B by the F-box protein Slimb/-TrCP. Genes Dev. 13:284.B kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103:351.[Medline]
(TrCP))-dependent ubiquitination of IB. Mol. Cell. Biol. 20:2326.This article has been cited by other articles:
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D. Fehr, C. Casanova, A. Liverman, H. Blazkova, K. Orth, D. Dobbelaere, J. Frey, and S. E. Burr AopP, a type III effector protein of Aeromonas salmonicida, inhibits the NF-{kappa}B signalling pathway. Microbiology, September 1, 2006; 152(Pt 9): 2809 - 2818. [Abstract] [Full Text] [PDF]
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J. E. Trosky, S. Mukherjee, D. L. Burdette, M. Roberts, L. McCarter, R. M. Siegel, and K. Orth Inhibition of MAPK Signaling Pathways by VopA from Vibrio parahaemolyticus J. Biol. Chem., December 10, 2004; 279(50): 51953 - 51957. [Abstract] [Full Text] [PDF]
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J. Sun, M. E. Hobert, A. S. Rao, A. S. Neish, and J. L. Madara Bacterial activation of {beta}-catenin signaling in human epithelia Am J Physiol Gastrointest Liver Physiol, July 1, 2004; 287(1): G220 - G227. [Abstract] [Full Text] [PDF]
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P. W. Lin, P. O. Simon Jr., A. T. Gewirtz, A. S. Neish, A. J. Ouellette, J. L. Madara, and W. I. Lencer Paneth Cell Cryptdins Act in Vitro as Apical Paracrine Regulators of the Innate Inflammatory Response J. Biol. Chem., May 7, 2004; 279(19): 19902 - 19907. [Abstract] [Full Text] [PDF]
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A. Haraga and S. I. Miller A Salmonella enterica Serovar Typhimurium Translocated Leucine-Rich Repeat Effector Protein Inhibits NF-{kappa}B-Dependent Gene Expression Infect. Immun., July 1, 2003; 71(7): 4052 - 4058. [Abstract] [Full Text] [PDF]
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S. Yoon, Z. Liu, Y. Eyobo, and K. Orth Yersinia Effector YopJ Inhibits Yeast MAPK Signaling Pathways by an Evolutionarily Conserved Mechanism J. Biol. Chem., January 17, 2003; 278(4): 2131 - 2135. [Abstract] [Full Text] [PDF]
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K. Chan, S. Baker, C. C. Kim, C. S. Detweiler, G. Dougan, and S. Falkow Genomic Comparison of Salmonella enterica Serovars and Salmonella bongori by Use of an S. enterica Serovar Typhimurium DNA Microarray J. Bacteriol., January 15, 2003; 185(2): 553 - 563. [Abstract] [Full Text] [PDF]
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