More than flipping the lid: Cdc50 contributes to echinocandin resistance by regulating calcium homeostasis in Cryptococcus neoformans
More than flipping the lid: Cdc50 contributes to echinocandin resistance by regulating calcium homeostasis in Cryptococcus neoformans
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DOI：
10.15698/mic2020.04.714
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发表时间：
2020-04-01
期刊：
影响因子：
4.6
通讯作者：
Xue, Chaoyang
中科院分区：
文献类型：
--
作者：
Cao, Chengjun;Xue, Chaoyang
棘白菌素是最新批准用于临床治疗常见侵袭性真菌病的杀菌药物。然而，它们对主要由新型隐球菌引起的隐球菌病无效。探讨了C.新生儿的情况还不清楚。我们知道Cdc 50，脂质移位酶（翻转酶）的β亚基，介导棘白菌素抗性，因为CDC 50基因的缺失使C.卡泊芬净是棘白菌素类的一种。我们试图阐明如何Cdc 50促进卡泊芬净耐药进行正向遗传筛选cdc 50。卡泊芬净耐药的抑制基因突变。我们鉴定了与Cdc 50功能相关的新型机械敏感性钙通道蛋白Crm 1（Cao et al.，2019年）。除了调节磷脂转运，Cdc 50还与Crm 1相互作用以调节细胞内钙稳态和钙/钙调神经磷酸酶信号，这可能驱动C.新人类我们的研究揭示了Cdc 50连接脂质翻转酶与钙信号传导的新的双重功能。这些意想不到的发现提供了新的见解棘白菌素耐药的机制，在C。可能推动未来药物设计的新型人。
Echinocandins are the newest fungicidal drug class approved for clinical use against common invasive mycoses. Yet, they are ineffective against cryptococcosis, predominantly caused by Cryptococcus neoformans. The underlying mechanisms of innate echinocandin resistance in C. neoformans remain unclear. We know that Cdc50, the beta-subunit of the lipid translocase (flippase), mediates echinocandin resistance, as loss of the CDC50 gene sensitizes C. neoformans to caspofungin, a member of the echinocandins class. We sought to elucidate how Cdc50 facilitates caspofungin resistance by performing a forward genetic screen for cdc50. suppressor mutations that are caspofungin resistant. We identified a novel mechanosensitive calcium channel protein Crm1 that correlates with Cdc50 function (Cao et al., 2019). In addition to regulating phospholipid translocation, Cdc50 also interacts with Crm1 to regulate intracellular calcium homeostasis and calcium/calcineurin signaling that likely drives caspofungin resistance in C. neoformans. Our study revealed a novel dual function of Cdc50 that connects lipid flippase with calcium signaling. These unexpected findings provide new insights into the mechanisms of echinocandin resistance in C. neoformans that may drive future drug design.