Characterization of an Nmr homolog that modulates GATA factor-mediated nitrogen metabolite repression in Cryptococcus neoformans.
Characterization of an Nmr homolog that modulates GATA factor-mediated nitrogen metabolite repression in Cryptococcus neoformans.
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DOI：
10.1371/journal.pone.0032585
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Fraser JA
中科院分区：
文献类型：
--
作者：
Lee IR;Lim JW;Ormerod KL;Morrow CA;Fraser JA
氮源利用在真菌发育、次生代谢产物产生和发病过程中起着关键作用。在子囊菌门和担子菌门中，GATA转录因子全局激活降解复杂氮化合物所需的分解代谢酶编码基因的表达。然而，在氨等首选氮源存在的情况下，GATA因子的活性在某些物种中通过与核磁共振共抑制蛋白的相互作用而受到抑制。这种调节现象，氮代谢物抑制，使易于同化的氮源优先利用。在担子菌病原体新型隐球菌中，除了氮分解代谢外，GATA因子Gat1/Are1还被用于调节多种关键的毒力性状。在这里，我们进一步表征了Gat1/Are1的功能，并研究了预测的核磁共振同源物Tar1的调控作用。虽然在氮限制期间诱导GAT1/ARE1表达，但TAR1的转录不受氮可用性的影响。在有利氮源存在的同时，TAR1的缺失会导致非首选氮分解代谢途径的不适当抑制。除了在抑制条件下表现出抑制GATA因子活性的进化保守作用外，Tar1在非抑制条件下也积极调节GAT1/ARE1的转录。然而，Tar1调节氮代谢物抑制的分子机制仍有待推测。在酵母双杂交实验中未检测到Tar1和Gat1/Are1之间的相互作用，这与Tar1和Gat1/Are1都缺乏已知相互作用的子囊菌核磁共振蛋白和GATA因子中存在的保守c端区域一致。重要的是，Tar1和Gat1/Are1都是新生芽孢杆菌毒力的抑制因子，重申并强调了氮调控发病机制的范式。
Nitrogen source utilization plays a critical role in fungal development, secondary metabolite production and pathogenesis. In both the Ascomycota and Basidiomycota, GATA transcription factors globally activate the expression of catabolic enzyme-encoding genes required to degrade complex nitrogenous compounds. However, in the presence of preferred nitrogen sources such as ammonium, GATA factor activity is inhibited in some species through interaction with co-repressor Nmr proteins. This regulatory phenomenon, nitrogen metabolite repression, enables preferential utilization of readily assimilated nitrogen sources. In the basidiomycete pathogen Cryptococcus neoformans, the GATA factor Gat1/Are1 has been co-opted into regulating multiple key virulence traits in addition to nitrogen catabolism. Here, we further characterize Gat1/Are1 function and investigate the regulatory role of the predicted Nmr homolog Tar1. While GAT1/ARE1 expression is induced during nitrogen limitation, TAR1 transcription is unaffected by nitrogen availability. Deletion of TAR1 leads to inappropriate derepression of non-preferred nitrogen catabolic pathways in the simultaneous presence of favoured sources. In addition to exhibiting its evolutionary conserved role of inhibiting GATA factor activity under repressing conditions, Tar1 also positively regulates GAT1/ARE1 transcription under non-repressing conditions. The molecular mechanism by which Tar1 modulates nitrogen metabolite repression, however, remains open to speculation. Interaction between Tar1 and Gat1/Are1 was undetectable in a yeast two-hybrid assay, consistent with Tar1 and Gat1/Are1 each lacking the conserved C-terminus regions present in ascomycete Nmr proteins and GATA factors that are known to interact with each other. Importantly, both Tar1 and Gat1/Are1 are suppressors of C. neoformans virulence, reiterating and highlighting the paradigm of nitrogen regulation of pathogenesis.
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