Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor Rim101p and protease Sap5p
Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor Rim101p and protease Sap5p
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DOI：
10.1128/iai.00054-07
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发表时间：
2007-05-01
影响因子：
3.1
通讯作者：
Dongari-Bagtzoglou, A.
中科院分区：
文献类型：
--
作者：
Villar, C. C.;Kashleva, H.;Dongari-Bagtzoglou, A.
白色念珠菌侵袭粘膜组织的能力是其主要的毒力决定因素，然而其侵袭机制尚不清楚。上皮细胞连接中的主要蛋白E-钙粘蛋白的蛋白水解分解已被提出为某些细菌在口腔粘膜中侵袭的机制。本研究的目的是（i）评估C。白色念珠菌降解E-钙粘蛋白表达的口腔上皮细胞在体外;（ii）比较不同的侵袭潜力菌株降解这种蛋白质的能力;和（iii）调查真菌毒力因子负责E-钙粘蛋白降解。我们发现，虽然E-钙粘蛋白基因表达没有改变，但在口腔上皮细胞与C.白色念珠菌此外，C.白念珠菌介导的E-钙粘蛋白的降解在蛋白酶抑制剂的存在下被完全抑制。利用人口腔粘膜的三维模型，我们发现E-钙粘蛋白在被C.白色念珠菌侵袭缺陷型rim 101（-）/rim 101（-）菌株在E-钙粘蛋白降解方面存在缺陷，这一发现表明蛋白酶可能依赖于Rim 101 p表达。事实上，逆转录-PCR数据表明，在rim 101（-）/rim 101（-）突变体中，SAP 4、SAP 5和SAP 6基因的表达严重降低。这些SAP基因是功能性Rim 101 p靶点，因为在rim 101（-）/rim 101（-）菌株中SAP 5的工程表达恢复了粘膜模型中的E-钙粘蛋白降解和侵袭。我们的数据支持这一假设，即有一种机制，通过C。白色念珠菌通过促进上皮粘附连接处的E-钙粘蛋白的蛋白水解降解而侵入粘膜组织。
The ability of Candida albicans to invade mucosal tissues is a major virulence determinant of this organism; however, the mechanism of invasion is not understood in detail. Proteolytic breakdown of E-cadherin, the major protein in epithelial cell junctions, has been proposed as a mechanism of invasion of certain bacteria in the oral mucosa. The objectives of this study were (i) to assess whether C. albicans degrades E-cadherin expressed by oral epithelial cells in vitro; (ii) to compare the abilities of strains with different invasive potentials to degrade this protein; and (iii) to investigate fungal virulence factors responsible for E-cadherin degradation. We found that while E-cadherin gene expression was not altered, E-cadherin was proteolytically degraded during the interaction of oral epithelial cells with C. albicans. Moreover, C. albicans-mediated degradation of E-cadherin was completely inhibited in the presence of protease inhibitors. Using a three-dimensional model of the human oral mucosa, we found that E-cadherin was degraded in localized areas of tissue invasion by C. albicans. An invasion-deficient rim101(-)/rim101(-) strain was deficient in degradation of E-cadherin, and this finding suggested that proteases may depend on Rim101p for expression. Indeed, reverse transcription-PCR data indicated that expression of the SAP4, SAP5, and SAP6 genes is severely reduced in the rim101(-)/rim101(-) mutant. These SAP genes are functional Rim101p targets, because engineered expression of SAP5 in the rim101(-)/rim101(-) strain restored E-cadherin degradation and invasion in the mucosal model. Our data support the hypothesis that there is a mechanism by which C. albicans invades mucosal tissues by promoting the proteolytic degradation of E-cadherin in epithelial adherens junctions.