Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans
Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans
复制标题
DOI：
10.1111/j.1365-2958.2007.05676.x
复制
发表时间：
2007-05-01
影响因子：
3.6
通讯作者：
Kwon-Chung, Kyung J.
中科院分区：
文献类型：
--
作者：
Chang, Yun C.;Bien, Clara M.;Kwon-Chung, Kyung J.
新型隐球菌是一种环境病原体，需要大气中的氧气水平才能实现最佳生长。吸入后，C.新型脑膜炎病毒传播到大脑并引起脑膜脑炎，但该病原体适应大脑中低氧环境的机制尚未得到研究。我们发现SRE1是哺乳动物固醇调节元件结合蛋白（SREBP）的同源物，在氧传感通路中发挥作用。低氧降低了C.新型和触发激活膜结合Sre1p的裂解激活蛋白，Scp1p。微阵列和北方印迹分析表明，在低氧下，Sre1 p激活麦角固醇生物合成和铁吸收所需的基因。与这些调节功能一致，sre 1 Delta细胞对唑类药物过敏，在铁限制条件下无法生长。重要的是，sre 1 Delta细胞未能在小鼠中产生暴发性脑感染。我们的体外数据支持一种模型，其中Sre1p在低氧下被激活，导致在营养限制环境中甾醇生物合成和生长所需的基因上调。动物研究证实了SRE 1对C.新型球菌适应宿主环境并引起致命性脑膜脑炎，从而鉴定SREBP途径作为隐球菌病的治疗靶点。
Cryptococcus neoformans is an environmental pathogen requiring atmospheric levels of oxygen for optimal growth. Upon inhalation, C. neoformans disseminates to the brain and causes meningoencephalitis, but the mechanisms by which the pathogen adapts to the low-oxygen environment in the brain have not been investigated. We found that SRE1, a homologue of the mammalian sterol regulatory element-binding protein (SREBP), functions in an oxygen-sensing pathway. Low oxygen decreased sterol synthesis in C. neoformans and triggered activation of membrane-bound Sre1p by the cleavage-activating protein, Scp1p. Microarray and Northern blot analysis demonstrated that under low oxygen, Sre1p activates genes required for ergosterol biosynthesis and iron uptake. Consistent with these regulatory functions, sre1 Delta cells were hypersensitive to azole drugs and failed to grow under iron-limiting conditions. Importantly, sre1 Delta cells failed to produce fulminating brain infection in mice. Our in vitro data support a model in which Sre1p is activated under low oxygen leading to the upregulation of genes required for sterol biosynthesis and growth in a nutrient-limiting environment. Animal studies confirm the importance of SRE1 for C. neoformans to adapt to the host environment and to cause fatal meningoencephalitis, thereby identifying the SREBP pathway as a therapeutic target for cryptococcosis.