Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.
Genetics. 2011 Jun;188(2):309-23. doi: 10.1534/genetics.111.128538. Epub 2011 Mar 24.
Proper regulation of metabolism is essential to maximizing fitness of organisms in their chosen environmental niche. Nitrogen metabolite repression is an example of a regulatory mechanism in fungi that enables preferential utilization of easily assimilated nitrogen sources, such as ammonium, to conserve resources. Here we provide genetic, transcriptional, and phenotypic evidence of nitrogen metabolite repression in the human pathogen Cryptococcus neoformans. In addition to loss of transcriptional activation of catabolic enzyme-encoding genes of the uric acid and proline assimilation pathways in the presence of ammonium, nitrogen metabolite repression also regulates the production of the virulence determinants capsule and melanin. Since GATA transcription factors are known to play a key role in nitrogen metabolite repression, bioinformatic analyses of the C. neoformans genome were undertaken and seven predicted GATA-type genes were identified. A screen of these deletion mutants revealed GAT1, encoding the only global transcription factor essential for utilization of a wide range of nitrogen sources, including uric acid, urea, and creatinine-three predominant nitrogen constituents found in the C. neoformans ecological niche. In addition to its evolutionarily conserved role in mediating nitrogen metabolite repression and controlling the expression of catabolic enzyme and permease-encoding genes, Gat1 also negatively regulates virulence traits, including infectious basidiospore production, melanin formation, and growth at high body temperature (39°-40°). Conversely, Gat1 positively regulates capsule production. A murine inhalation model of cryptococcosis revealed that the gat1Δ mutant is slightly more virulent than wild type, indicating that Gat1 plays a complex regulatory role during infection.
适当的代谢调控对于生物体在其选择的生态位中最大限度地发挥适应性至关重要。氮代谢物抑制是真菌中一种调节机制的示例，它使生物体能够优先利用易于同化的氮源，如铵盐，以节约资源。在这里，我们提供了人类病原体新型隐球菌中氮代谢物抑制的遗传、转录和表型证据。除了在铵存在的情况下，尿酸和脯氨酸同化途径的分解代谢酶编码基因的转录激活丧失外，氮代谢物抑制还调节了毒力决定因素荚膜和黑色素的产生。由于 GATA 转录因子已知在氮代谢物抑制中发挥关键作用，因此对新型隐球菌基因组进行了生物信息学分析，鉴定了七个预测的 GATA 型基因。对这些缺失突变体的筛选揭示了 GAT1，它编码唯一的全局转录因子，对于利用广泛的氮源（包括尿酸、尿素和肌酐——新型隐球菌生态位中发现的三种主要氮成分）是必需的。除了在介导氮代谢物抑制和控制分解代谢酶和渗透酶编码基因的表达方面的进化保守作用外，Gat1 还负调控毒力特征，包括感染性担子孢子的产生、黑色素的形成以及在高温（39°-40°）下的生长。相反，Gat1 正调控荚膜的产生。新型隐球菌 cryptococcosis 的小鼠吸入模型表明，gat1Δ 突变体比野生型略具毒力，表明 Gat1 在感染过程中发挥了复杂的调节作用。
