The sphingolipid pathway regulates Pkc1 through the formation of diacylglycerol in Cryptococcus neoformans
The sphingolipid pathway regulates Pkc1 through the formation of diacylglycerol in Cryptococcus neoformans
复制标题
DOI：
10.1074/jbc.m312995200
复制
发表时间：
2004-05-14
影响因子：
4.8
通讯作者：
Del Poeta, M
中科院分区：
文献类型：
--
作者：
Heung, LJ;Luberto, C;Del Poeta, M
鞘脂生物合成途径产生对调节哺乳动物和真菌生理和病理生物学过程至关重要的生物活性分子。在以前的研究中（Luberto，C.，Toffaletti，D. L.，Wills，E.一、塔克，S。C.的方法，Casadevall，A.，太好了，J. R.，Hannun，Y.一、和Del Poeta，M.（2001）Genes Dev. 15，201-212），我们证明了真菌鞘脂途径的酶Ipc 1（肌醇-磷酸神经酰胺合酶-1）调节黑色素，黑色素是致病真菌新型隐球菌引起疾病所需的色素。在这项研究中，我们研究了Ipc 1调节黑色素产生的机制。因为Ipc 1也催化二酰基甘油（DAG）的产生，DAG是哺乳动物蛋白激酶C（PKC）的经典和新型亚型的生理激活剂，并且因为已经表明PKC是哺乳动物细胞中黑素生成所必需的，所以我们研究了Ipc 1是否调节C.通过产生DAG和随后激活Pkc 1（哺乳动物PKC的真菌同源物）来诱导新生菌。结果表明，Ipc 1的调节可调节C.新生细胞接下来，我们证明了C。Pkc 1是DAG激活的丝氨酸/苏氨酸激酶，并且Pkc 1的C1结构域对于这种激活是必需的。最后，通过药理学和遗传学方法，我们发现抑制Pkc 1可以消除C.新人类本研究确定了一种新的信号通路，其中C。新生儿Ipc 1通过DAG的形成在Pkc 1的激活中起关键作用。重要的是，这一途径是必不可少的黑色素的生产与暗示的致病性的C。新人类
The sphingolipid biosynthetic pathway generates bioactive molecules crucial to the regulation of mammalian and fungal physiological and pathobiological processes. In previous studies (Luberto, C., Toffaletti, D. L., Wills, E. A., Tucker, S. C., Casadevall, A., Perfect, J. R., Hannun, Y. A., and Del Poeta, M. (2001) Genes Dev. 15, 201-212), we demonstrated that an enzyme of the fungal sphingolipid pathway, Ipc1 (inositol-phosphorylceramide synthase-1), regulates melanin, a pigment required for the pathogenic fungus Cryptococcus neoformans to cause disease. In this study, we investigated the mechanism by which Ipc1 regulates melanin production. Because Ipc1 also catalyzes the production of diacylglycerol (DAG), a physiological activator of the classical and novel isoforms of mammalian protein kinase C (PKC), and because it has been suggested that PKC is required for melanogenesis in mammalian cells, we investigated whether Ipc1 regulates melanin in C. neoformans through the production of DAG and the subsequent activation of Pkc1, the fungal homolog of mammalian PKC. The results show that modulation of Ipc1 regulates the levels of DAG in C. neoformans cells. Next, we demonstrated that C. neoformans Pkc1 is a DAG-activated serine/threonine kinase and that the C1 domain of Pkc1 is necessary for this activation. Finally, through both pharmacological and genetic approaches, we found that inhibition of Pkc1 abolishes melanin formation in C. neoformans. This study identifies a novel signaling pathway in which C. neoformans Ipc1 plays a key role in the activation of Pkc1 through the formation of DAG. Importantly, this pathway is essential for melanin production with implications for the pathogenicity of C. neoformans.