Lee Hyeseung, Chang Yun C, Varma Ashok, Kwon-Chung Kyung J
Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases/NIH, Bethesda, MD 20892, USA.
Eukaryot Cell. 2009 Dec;8(12):1901-8. doi: 10.1128/EC.00256-09. Epub 2009 Oct 9.
Cryptococcus neoformans serotype A strains, the major cause of cryptococcosis, are distributed worldwide, while serotype D strains are more concentrated in Central Europe. We have previously shown that deletion of the global regulator TUP1 in serotype D isolates results in a novel peptide-mediated, density-dependent growth phenotype that mimics quorum sensing and is not known to exist in other fungi. Unlike for tup1Delta strains of serotype D, the density-dependent growth phenotype was found to be absent in tup1Delta strains of serotype A which had been derived from several different genetic clusters. The serotype A H99 tup1Delta strain showed less retardation in the growth rate than tup1Delta strains of serotype D, but the mating efficiency was found to be similar in both serotypes. Deletion of TUP1 in the H99 strain resulted in significantly enhanced capsule production and defective melanin formation and also revealed a unique regulatory role of the TUP1 gene in maintaining iron/copper homeostasis. Differential expression of various genes involved in capsule formation and iron/copper homeostasis was observed between the wild-type and tup1Delta H99 strains. Furthermore, the H99 tup1Delta strain displayed pleiotropic effects which included sensitivity to sodium dodecyl sulfate, susceptibility to fluconazole, and attenuated virulence. These results demonstrate that the global regulator TUP1 has pathobiological significance and plays both conserved and distinct roles in serotype A and D strains of C. neoformans.
新型隐球菌A血清型菌株是隐球菌病的主要病因，分布于全球，而D血清型菌株则更集中在中欧。我们之前已经表明，在D血清型分离株中缺失全局调节因子TUP1会导致一种新的肽介导的、密度依赖性生长表型，这种表型模拟群体感应，在其他真菌中不存在。与D血清型的tup1Δ菌株不同，来自几个不同基因簇的A血清型tup1Δ菌株中不存在密度依赖性生长表型。A血清型H99 tup1Δ菌株的生长速率比D血清型的tup1Δ菌株受抑制程度小，但发现两种血清型的交配效率相似。在H99菌株中缺失TUP1导致荚膜产量显著增加和黑色素形成缺陷，还揭示了TUP1基因在维持铁/铜稳态中的独特调节作用。在野生型和tup1Δ H99菌株之间观察到参与荚膜形成和铁/铜稳态的各种基因的差异表达。此外，H99 tup1Δ菌株表现出多效性，包括对十二烷基硫酸钠敏感、对氟康唑敏感和毒力减弱。这些结果表明，全局调节因子TUP1具有病理生物学意义，在新型隐球菌的A血清型和D血清型菌株中发挥着保守和独特的作用。
