Mamouei Zeinab, Zeng Guisheng, Wang Yan-Ming, Wang Yue
Multi-Modal Molecular (M3) Biology, Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Mol Microbiol. 2017 Dec;106(6):986-998. doi: 10.1111/mmi.13864. Epub 2017 Nov 2.
Iron is an essential nutrient for nearly all organisms, but iron overdose is toxic. The human commensal-pathogenic fungus Candida albicans traverses host niches with markedly different iron availability. During systemic infection, C. albicans must activate the high-affinity iron permease Ftr1 to acquire iron sequestered by the host's iron-withholding defense and suppresses iron uptake while residing in the iron-rich gut to avoid toxicity. Ftr1 associates with a ferroxidase to form an iron transporter. C. albicans contains four permeases and five ferroxidase homologs, suggesting 20 possible subunit combinations. Here, we investigated the iron-dependent expression, cellular localization and interacting partners of all permeases and ferroxidases and the significance of each subunit for gastrointestinal colonization and systemic infection in mice. We uncovered three distinct patterns of iron-dependent expression and highly flexible ferroxidase-permease partnerships, which underlie a dynamic iron transport system that can be deftly tuned according to iron availability. We found functional differentiation as well as redundancy among the ferroxidases and permeases during both gastrointestinal colonization and bloodstream infection. We propose that C. albicans possesses a sophisticated iron acquisition and utilization system befitting its commensal-pathogenic lifestyle. Our findings reveal new possibilities for medical intervention of C. albicans infection.
铁是几乎所有生物体必需的营养素，但铁过量具有毒性。人类共生致病真菌白色念珠菌穿越铁可用性明显不同的宿主生态位。在全身感染期间，白色念珠菌必须激活高亲和力铁通透酶Ftr1以获取被宿主铁扣留防御所隔离的铁，并在驻留在富含铁的肠道中时抑制铁的摄取以避免毒性。Ftr1与一种铁氧化酶结合形成一种铁转运体。白色念珠菌含有四种通透酶和五种铁氧化酶同源物，提示有20种可能的亚基组合。在这里，我们研究了所有通透酶和铁氧化酶的铁依赖性表达、细胞定位和相互作用伙伴，以及每个亚基对小鼠胃肠道定植和全身感染的意义。我们发现了三种不同的铁依赖性表达模式和高度灵活的铁氧化酶-通透酶伙伴关系，它们构成了一个动态铁转运系统，该系统可根据铁的可用性进行巧妙调节。我们发现在胃肠道定植和血流感染过程中，铁氧化酶和通透酶之间存在功能分化以及冗余。我们提出白色念珠菌拥有一个与其共生致病生活方式相适应的复杂铁获取和利用系统。我们的发现揭示了白色念珠菌感染医学干预的新可能性。
