Diverse Hap43-Independent Functions of the Candida albicans CCAAT-Binding Complex
Diverse Hap43-Independent Functions of the Candida albicans CCAAT-Binding Complex
复制标题
DOI：
10.1128/ec.00014-13
复制
发表时间：
2013-06-01
期刊：
影响因子：
--
通讯作者：
Lan, Chung-Yu
中科院分区：
文献类型：
--
作者：
Hsu, Po-Chen;Chao, Chun-Cheih;Lan, Chung-Yu
CCAAT基序普遍存在于真核基因组的启动子中。CCAAT结合复合物（CBC）在广泛的生物体中是保守的，特异性识别CCAAT基序，并直接或与其他转录因子合作调节转录。在白色念珠菌中，CBC已知与阻遏物Hap 43相互作用以负调节铁利用基因以响应铁剥夺。然而，CBC的额外功能的范围尚不清楚。在这项研究中，我们探讨了CBC在C。白念珠菌并发现CBC在体外多效性调节许多毒力性状，包括负控制负责核糖体生物发生和翻译的基因以及正调节低氮诱导的成丝。此外，C.白念珠菌CBC参与利用宿主蛋白质作为氮源以及抑制细胞絮凝和粘附素基因表达。此外，我们的上位性分析表明，CBC作为Rhb 1-TOR信号的下游效应器，并通过Mep 2-Ras 1-蛋白激酶A（PKA）/丝裂原活化蛋白激酶（MAPK）途径控制低氮诱导的抑制。重要的是，这里鉴定的表型都独立于Hap 43。最后，编码CBC组分的基因的缺失使C.在斑马鱼和小鼠感染模型中的白色念珠菌毒力。因此，我们的研究结果突出了C.白念珠菌CBC在调节多种毒力性状，以应对环境扰动，最后，建议抗真菌治疗的潜在目标，以及扩大我们对其他真菌病原体的发病机制的理解。
The CCAAT motif is ubiquitous in promoters of eukaryotic genomes. The CCAAT-binding complex (CBC) is conserved across a wide range of organisms, specifically recognizes the CCAAT motif, and modulates transcription directly or in cooperation with other transcription factors. In Candida albicans, CBC is known to interact with the repressor Hap43 to negatively regulate iron utilization genes in response to iron deprivation. However, the extent of additional functions of CBC is unclear. In this study, we explored new roles of CBC in C. albicans and found that CBC pleiotropically regulates many virulence traits in vitro, including negative control of genes responsible for ribosome biogenesis and translation and positive regulation of low-nitrogen-induced filamentation. In addition, C. albicans CBC is involved in utilization of host proteins as nitrogen sources and in repression of cellular flocculation and adhesin gene expression. Moreover, our epistasis analyses suggest that CBC acts as a downstream effector of Rhb1-TOR signaling and controls low-nitrogen-induced filamentation via the Mep2-Ras1-protein kinase A (PKA)/mitogen-activated protein kinase (MAPK) pathway. Importantly, the phenotypes identified here are all independent of Hap43. Finally, deletion of genes encoding CBC components slightly attenuated C. albicans virulence in both zebrafish and murine models of infection. Our results thus highlight new roles of C. albicans CBC in regulating multiple virulence traits in response to environmental perturbations and, finally, suggest potential targets for antifungal therapies as well as extending our understanding of the pathogenesis of other fungal pathogens.