Endoplasmic reticulum localized PerA is required for cell wall integrity, azole drug resistance, and virulence in Aspergillus fumigatus.
Endoplasmic reticulum localized PerA is required for cell wall integrity, azole drug resistance, and virulence in Aspergillus fumigatus.
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DOI：
10.1111/mmi.12626
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发表时间：
2014-06
影响因子：
3.6
通讯作者：
Cramer RA
中科院分区：
文献类型：
--
作者：
Chung D;Thammahong A;Shepardson KM;Blosser SJ;Cramer RA
gpi锚定是真核生物翻译后蛋白修饰的一种普遍而关键的方法。在真菌中，许多细胞壁蛋白是gpi锚定的，gpi锚定蛋白的破坏会损害细胞壁的完整性。GPI锚点合成并附着于靶蛋白后，对脂质部分进行修饰。尽管它对GPI锚定蛋白功能很重要，但我们目前对致病真菌中GPI脂质重塑的了解有限。在这项研究中，我们鉴定了推定的GPI脂质重塑蛋白PerA在人类致病真菌烟曲霉中的作用。PerA定位于内质网，PerA的缺失会导致细胞壁完整性的显著缺陷。perA null突变体减少了分生孢子的产生，增加了对三唑类抗真菌药物的敏感性，并且在侵袭性肺曲霉病小鼠模型中是无毒的。有趣的是，PerA的缺失增加了菌丝细胞表面β-葡聚糖和几丁质含量的暴露，但相对于野生型，骨髓源性巨噬细胞产生的TNF减少。鉴于真菌GPI锚点的结构特异性不同于人类，了解烟曲霉GPI脂质重塑和PerA功能是发现新的真菌特异性抗真菌药物靶点的一个有前景的研究方向。
GPI-anchoring is a universal and critical post-translational protein modification in eukaryotes. In fungi, many cell wall proteins are GPI-anchored, and disruption of GPI-anchored proteins impairs cell wall integrity. After being synthesized and attached to target proteins, GPI anchors undergo modification on lipid moieties. In spite of its importance for GPI-anchored protein functions, our current knowledge of GPI lipid remodeling in pathogenic fungi is limited. In this study, we characterized the role of a putative GPI lipid remodeling protein, designated PerA, in the human pathogenic fungus Aspergillus fumigatus. PerA localizes to the endoplasmic reticulum and loss of PerA leads to striking defects in cell wall integrity. A perA null mutant has decreased conidia production, increased susceptibility to triazole antifungal drugs, and is avirulent in a murine model of invasive pulmonary aspergillosis. Interestingly, loss of PerA increases exposure of β-glucan and chitin content on the hyphal cell surface, but diminished TNF production by bone marrow derived macrophages relative to wild type. Given the structural specificity of fungal GPI-anchors, which is different from humans, understanding GPI lipid remodeling and PerA function in A. fumigatus is a promising research direction to uncover a new fungal specific antifungal drug target.
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影响因子：
4.4
作者：
Bozza, Silvia;Clavaud, Cecile;Romani, Luigina
通讯作者：
Romani, Luigina
影响因子：
2.8
作者：
Chai, Louis Y. A.;Netea, Mihai G.;Sugui, Janyce;Vonk, Alieke G.;van de Sande, Wendy W. J.;Warris, Adilia;Kwon-Chung, Kyung J.;Kullberg, Bart Jan
通讯作者：
Kullberg, Bart Jan
影响因子：
64.8
作者：
Aimanianda, Vishukumar;Bayry, Jagadeesh;Latge, Jean-Paul
通讯作者：
Latge, Jean-Paul
影响因子：
4.3
作者：
Fontaine, T;Magnin, T;Ferguson, MAJ
通讯作者：
Ferguson, MAJ
影响因子：
6.7
作者：
Beauvais A;Bozza S;Kniemeyer O;Formosa C;Balloy V;Henry C;Roberson RW;Dague E;Chignard M;Brakhage AA;Romani L;Latgé JP
通讯作者：
Latgé JP