A defect in ATP-citrate lyase links acetyl-CoA production, virulence factor elaboration and virulence in Cryptococcus neoformans.
A defect in ATP-citrate lyase links acetyl-CoA production, virulence factor elaboration and virulence in Cryptococcus neoformans.
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DOI：
10.1111/mmi.12065
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发表时间：
2012-12
影响因子：
3.6
通讯作者：
Kronstad JW
中科院分区：
文献类型：
--
作者：
Griffiths EJ;Hu G;Fries B;Caza M;Wang J;Gsponer J;Gates-Hollingsworth MA;Kozel TR;De Repentigny L;Kronstad JW
新生隐球菌与先天免疫系统吞噬细胞的相互作用是导致免疫功能低下个体脑膜脑炎的播散性疾病的关键步骤。从细胞培养基或巨噬细胞中收获的隐球菌细胞的转录谱发现真菌适应细胞内环境期间代谢和其他功能的差异表达。我们专注于ATP-柠檬酸裂解酶的ACL 1基因，该酶将柠檬酸转化为乙酰辅酶A，因为该基因在巨噬细胞中显示出升高的转录水平，并且因为乙酰辅酶A作为中心代谢物的重要性。缺乏ACL 1的突变体在含有葡萄糖的培养基上生长延迟，乙酰辅酶A的细胞水平降低，毒力因子的产生缺陷，对抗真菌药物氟康唑的敏感性增加，巨噬细胞内的存活率降低。重要的是，acl 1突变体不能在小鼠吸入模型中引起疾病，这是一种比乙酰辅酶A产生缺陷的其他突变体更极端的表型（例如，乙酰辅酶A合成酶突变体）。毒力的丧失可能是由于C.新人类隐球菌Acl 1的系统发育分析和结构建模确定了真菌蛋白序列所特有的三个indel;这些差异可能为开发病原体特异性抑制剂提供机会。
The interaction of Cryptococcus neoformans with phagocytic cells of the innate immune system is a key step in disseminated disease leading to meningoencephalitis in immunocompromised individuals. Transcriptional profiling of cryptococcal cells harvested from cell culture medium or from macrophages found differential expression of metabolic and other functions during fungal adaptation to the intracellular environment. We focused on the ACL1 gene for ATP-citrate lyase, which converts citrate to acetyl-CoA, because this gene showed elevated transcript levels in macrophages and because of the importance of acetyl-CoA as a central metabolite. Mutants lacking ACL1 showed delayed growth on medium containing glucose, reduced cellular levels of acetyl-CoA, defective production of virulence factors, increased susceptibility to the antifungal drug fluconazole and decreased survival within macrophages. Importantly, acl1 mutants were unable to cause disease in a murine inhalation model, a phenotype that was more extreme than other mutants with defects in acetyl-CoA production (e.g., an acetyl-CoA synthetase mutant). Loss of virulence is likely due to perturbation of critical physiological interconnections between virulence factor expression and metabolism in C. neoformans. Phylogenetic analysis and structural modeling of cryptococcal Acl1 identified three indels unique to fungal protein sequences; these differences may provide opportunities for the development of pathogen-specific inhibitors.
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DOI：
10.1083/jcb.200901145
发表时间：
2009-05-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Klemm RW;Ejsing CS;Surma MA;Kaiser HJ;Gerl MJ;Sampaio JL;de Robillard Q;Ferguson C;Proszynski TJ;Shevchenko A;Simons K
通讯作者：
Simons K
影响因子：
64.5
作者：
Mousley CJ;Yuan P;Gaur NA;Trettin KD;Nile AH;Deminoff SJ;Dewar BJ;Wolpert M;Macdonald JM;Herman PK;Hinnebusch AG;Bankaitis VA
通讯作者：
Bankaitis VA
影响因子：
--
作者：
Hynes, Michael J.;Murray, Sandra L.
通讯作者：
Murray, Sandra L.
影响因子：
3.1
作者：
Kozel, TR;Levitz, SM;Janbon, G
通讯作者：
Janbon, G
影响因子：
--
作者：
Moyrand, Frederique;Lafontaine, Ingrid;Janbon, Guilhem
通讯作者：
Janbon, Guilhem