Huang Xinhua, Chen Xiaoqing, He Yongmin, Yu Xiaoyu, Li Shanshan, Gao Ning, Niu Lida, Mao Yinhe, Wang Yuanyuan, Wu Xianwei, Wu Wenjuan, Wu Jianhua, Zhou Dongsheng, Zhan Xiangjiang, Chen Changbin
Unit of Pathogenic Fungal Infection & Host Immunity, CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
College of Life Science, Shanghai University, Shanghai, China.
PLoS Pathog. 2017 Jun 1;13(6):e1006414. doi: 10.1371/journal.ppat.1006414. eCollection 2017 Jun.
Efficient assimilation of alternative carbon sources in glucose-limited host niches is critical for colonization of Candida albicans, a commensal yeast that frequently causes opportunistic infection in human. C. albicans evolved mechanistically to regulate alternative carbon assimilation for the promotion of fungal growth and commensalism in mammalian hosts. However, this highly adaptive mechanism that C. albicans employs to cope with alternative carbon assimilation has yet to be clearly understood. Here we identified a novel role of C. albicans mitochondrial complex I (CI) in regulating assimilation of alternative carbon sources such as mannitol. Our data demonstrate that CI dysfunction by deleting the subunit Nuo2 decreases the level of NAD+, downregulates the NAD+-dependent mannitol dehydrogenase activity, and consequently inhibits hyphal growth and biofilm formation in conditions when the carbon source is mannitol, but not fermentative sugars like glucose. Mannitol-dependent morphogenesis is controlled by a ROS-induced signaling pathway involving Hog1 activation and Brg1 repression. In vivo studies show that nuo2Δ/Δ mutant cells are severely compromised in gastrointestinal colonization and the defect can be rescued by a glucose-rich diet. Thus, our findings unravel a mechanism by which C. albicans regulates carbon flexibility and commensalism. Alternative carbon assimilation might represent a fitness advantage for commensal fungi in successful colonization of host niches.
在葡萄糖受限的宿主生态位中高效同化替代碳源对于白色念珠菌的定殖至关重要，白色念珠菌是一种共生酵母，经常在人类中引起机会性感染。白色念珠菌通过机制进化来调节替代碳同化，以促进真菌在哺乳动物宿主中的生长和共生。然而，白色念珠菌用于应对替代碳同化的这种高度适应性机制尚未得到清楚的了解。在这里，我们确定了白色念珠菌线粒体复合物I（CI）在调节替代碳源（如甘露醇）同化中的新作用。我们的数据表明，通过缺失亚基Nuo2导致的CI功能障碍会降低NAD+水平，下调NAD+依赖性甘露醇脱氢酶活性，从而在碳源为甘露醇而非葡萄糖等发酵糖的条件下抑制菌丝生长和生物膜形成。依赖甘露醇的形态发生受涉及Hog1激活和Brg1抑制的ROS诱导信号通路控制。体内研究表明，nuo2Δ/Δ突变细胞在胃肠道定殖中严重受损，富含葡萄糖的饮食可以挽救这种缺陷。因此，我们的发现揭示了白色念珠菌调节碳灵活性和共生的机制。替代碳同化可能代表共生真菌在成功定殖宿主生态位方面的适应性优势。
