Host Resistance to Lung Infection Mediated by Major Vault Protein in Epithelial Cells

Kowalski, Michael P.; Dubouix-Bourandy, Anne; Bajmoczi, Milan; Golan, David E.; Zaidi, Tanweer; Coutinho-Sledge, Yamara S.; Gygi, Melanie P.; Gygi, Steven P.; Wiemer, Erik A.C.; Pier, Gerald B.

doi:10.1126/science.1142311

Cited by 124 publications

(142 citation statements)

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“…In transgenic CFTR-knockout mice, NF-κB nuclear translocation occurs much later in the airway epithelial cells [28], probably contributing more to the harmful inflammation that ensues in this environment instead of the protective inflammation that occurs when functional CFTR is present. Overall, this scenario wherein WT-CFTR binding of P. aeruginosa leads to protection and failure of this interaction in CF leads to infection is supported by data obtained in numerous in vitro and, importantly, in υivo, studies demonstrating CFTR-dependent responses to P. aeruginosa in a variety of lung epithelial cell lines and in transgenic animals [8][9][10][11][12][27][28][29]31,36]. Thus, it seems that CFTR facilitates bacterial clearance and modulates innate immunity towards P. aeruginosa in lung epithelial cells by being the linchpin needed for coordinating multiple host responses involved in resisting infection and maintaining tissue homeostasis in the long run.…”

mentioning

confidence: 76%

“…Overall, this scenario wherein WT-CFTR binding of P. aeruginosa leads to protection and failure of this interaction in CF leads to infection is supported by data obtained in numerous in vitro and, importantly, in υivo, studies demonstrating CFTR-dependent responses to P. aeruginosa in a variety of lung epithelial cell lines and in transgenic animals [8][9][10][11][12][27][28][29]31,36]. Thus, it seems that CFTR facilitates bacterial clearance and modulates innate immunity towards P. aeruginosa in lung epithelial cells by being the linchpin needed for coordinating multiple host responses involved in resisting infection and maintaining tissue homeostasis in the long run.A recent approach to determine the molecular components that govern the CFTR-dependent epithelial cell responses to P. aeruginosa has utilized an analysis of host proteins recruited to lipid rafts in human airway epithelial cells within 15 min of infection with P. aeruginosa [36]. About 150 proteins were identified by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry analysis that were present exclusively in the P. aeruginosa-induced rafts.…”

mentioning

confidence: 76%

“…A recent approach to determine the molecular components that govern the CFTR-dependent epithelial cell responses to P. aeruginosa has utilized an analysis of host proteins recruited to lipid rafts in human airway epithelial cells within 15 min of infection with P. aeruginosa [36]. About 150 proteins were identified by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry analysis that were present exclusively in the P. aeruginosa-induced rafts.…”

Section: Host Factors Allowing P Aeruginosa To Initiate Infection Inmentioning

confidence: 99%

“…Components of the protective, CFTRdependent response include (i) rapid release of IL-1 and signaling through the IL-1 receptor and the adaptor molecule MyD88 to initiate NF-κB nuclear translocation, (ii) formation of lipid rafts containing P. aeruginosa bound to CFTR, (iii) transcription of genes and production of proinflammatory proteins to recruit polymorphonuclear leukocytes (PMNLs) to the airway surface, (iv) elimination of P. aeruginosa by desquamation of epithelial cells with internalized bacteria and phagocytic killing by PMNLs and (v) resolution of infection via apoptosis of the epithelial cells and PMNLs that have encountered P. aeruginosa. Within the lipid raft are up to 150 proteins that are not found in lipid rafts of infected airway epithelial cells containing mutant-CFTR, and several of these, notably MVP [36], are key participants in fullfledged resistance to P. aeruginosa infection. Of importance, virtually all of the findings related to the recognition of P. aeruginosa by CFTR have been validated in appropriate animal models, are consistent with the analysis of infection in CF lung samples and explain why this one pathogen, P. aeruginosa, is the overwhelmingly dominant cause of morbidity and the life-shortening mortality due to respiratory failure in CF.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

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Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

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Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism. Pseudomonas aeruginosa in cystic fibrosisCystic fibrosis (CF) is unique among human genetic disorders in that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein whose primary function described to date has been to regulate conductance of ions in and out of cells and intracellular vacuoles, lead to hypersusceptibility to chronic lung infection. Human diseases wherein individuals homozygous for mutant genes are predisposed to infections serve as a firm foundation for understanding the molecular, cellular, physiologic and immunologic aspects of normal and compromised resistance to infection. CF is not just a prime example of how we can learn about normal and pathologic states; it could, in fact, be the only known human genetically determined disease wherein infection with a single pathogen -Pseudomonas aeruginosa -drives the vast majority of morbidity, clinical deterioration and ultimately life-shortening mortality encountered in this disease. In humans with significant compromises to their immune system, such as advanced AIDS, we would normally expect to see a plethora of pathogens take advantage of this debilitated state, but this is not the case in CF.CF is characterized by the emergence and persistence of (and, ultimately, the inability to clear) chronic infection with a variant of P. aeruginosa (mucoid P. aeruginosa) that overproduces a surface polysaccharide known as alginate. The organism undergoes other significant genetic adaptations and selections within the CF lung, and it is the emergence of mucoid P. aeruginosa that is the primary determinant of the clinical course of this disease [1,2]. In those individuals with either an uncommon but fortuitous protective immune response to specific P. aeruginosa antigens [3,4] Histopathologic basis for defining relevant interactions between P.aeruginosa and the CF airway epitheliumAlthough CF is a multisystem disease characterized by GI and nutritional abnormalities, salt loss syndromes and male urogenital abnormalities, the major clinical problem for CF patients is chronic sinopulmonary disease. Therefore, relying on observations made fr...

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mentioning

confidence: 76%

mentioning

confidence: 76%

Section: Host Factors Allowing P Aeruginosa To Initiate Infection Inmentioning

confidence: 99%

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

See 2 more Smart Citations

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

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100

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“…10 MVP expression has also been shown to be induced by histone deacetylase inhibitors such as sodium butyrate, 11 phorbol 12-myristate 13-acetate (PMA) and cytarabine 12 as well as by cytotoxic drugs. [12][13][14] MVP/vaults have been proposed to be important in intracellular transport, [15][16][17] innate immunity 18 and virus infection. 19 Several studies demonstrated that MVP is important in cell signaling [20][21][22] and in cell survival.…”

mentioning

confidence: 99%

On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis

Ryu

et al. 2008

Cell Death Differ

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Major vault protein (MVP), the main component of vault complex, is overexpressed in many multidrug-resistant cancer cell lines, suggesting a possible role for MVP in cell signaling and survival. In this study, we have found that MVP is markedly increased in senescent human diploid fibroblasts (HDFs) as well as in aged organs. We examined whether MVP expression might be affected by apoptotic stress in an aging-dependent manner. We treated young and senescent HDFs with apoptosis-inducing agents such as H 2 O 2 , staurosporine and thapsigargin, and monitored MVP expression. We found that MVP expression is markedly reduced in young HDFs but not in senescent HDFs, in response to apoptotic stresses. Downregulation of MVP increased the sensitivity of senescent HDFs to apoptosis. Also, the level of antiapoptotic B-cell lymphoma protein-2 (Bcl-2) was significantly reduced and the accumulation of c-Jun increased in MVP knocked-down senescent HDFs. Moreover, treatment of MVP knocked-down senescent HDFs with SP600125, a specific c-Jun NH (2) Vaults are large ribonucleoprotein particles found in a great portion of eukaryotic cells. The vault particle is a multimeric structure composed of three proteins -the major vault protein (MVP), two minor vault proteins, vault poly (ADP-ribose) polymerase (VPARP) and telomerase-associated protein-1 (TP-1), and four small untranslated vault RNAs (vRNAs). 1 MVP is the main component of the vault complex accounting for 75% of the total particle mass. 2 The vault particle has been so named because it has a barrel-shaped structure, reminiscent of the vaulted ceilings in cathedrals. 3 The interaction of MVP by its coiled coil domain is involved in the formation of the basic vault complex. 4 MVP expression is upregulated in cancers such as melanoma, 5 colon cancer 6 and gliomas 7 during acquisition of multidrug resistance 8,9 and during differentiation of dendritic cells. 10 MVP expression has also been shown to be induced by histone deacetylase inhibitors such as sodium butyrate, 11 phorbol 12-myristate 13-acetate (PMA) and cytarabine 12 as well as by cytotoxic drugs. 12-14 MVP/vaults have been proposed to be important in intracellular transport, 15-17 innate immunity 18 and virus infection. 19 Several studies demonstrated that MVP is important in cell signaling [20][21][22] and in cell survival. 10,20,23 For example, serumdeprived MVP-deficient mouse embryonic fibroblasts (MEFs) exhibit significantly increased cell death when compared with wild-type MEFs. 20 Therefore, the role of MVP as a scaffolding protein for signaling proteins, especially for cell survival, has received more attention than as a transport vehicle. However, the exact role of MVP in cell survival is not well understood. In this study, we found that apoptotic resistance of senescent human diploid fibroblasts (HDFs) correlates with the increased content of MVP in the senescent cells. This is the first report implicating MVP in apoptosis resistance of senescent HDFs. ResultsIncreased expression of MVP in aged cells and organs...

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Age associated high level of major vault protein is p53 dependent

Ryu

Kim

et al. 2009

Cell Biochemistry & Function

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Major vault protein (MVP) represents the main component of vaults and has been linked to multi-drug resistance (MDR) in cancer cells. We previously reported that MVP plays an important role in the resistance of senescent human diploid fibroblasts (HDFs) to apoptosis and also that MVP expression is markedly reduced in young HDFs but not in senescent HDFs. In this study, designed to elucidate the regulation of MVP in young and senescent HDFs, we examined the levels of transcriptional factors for the MVP gene, which revealed that among the putative transcriptional factors, p53 decreased only in young HDFs, but not in senescent HDFs in response to H(2)O(2) treatment in the same mode as the expression of MVP. Moreover, the phosphorylation status of p53 increased only in senescent HDFs but not in young HDFs in response to H(2)O(2) treatment. Therefore, we tested the possibility of MVP regulation by p53 status. MVP is upregulated in p53 over-expressing young HDFs, while MVP is downregulated in p53-specific small interfering RNA (siRNA)-transfected senescent HDFs, which suggests that the expression of MVP would be p53 dependent. Furthermore, using chromatin immunoprecipitation (ChIP) assay, we observed that p53 binds directly to the MVP promoter. Taken together, these results suggest that p53 would be a major transcriptional factor for MVP gene expression.

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Host Resistance to Lung Infection Mediated by Major Vault Protein in Epithelial Cells

Cited by 124 publications

References 32 publications

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis

Age associated high level of major vault protein is p53 dependent

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