Candida albicans responds to glycostructure damage by Ace2-mediated feedback regulation of Cek1 signaling
Candida albicans responds to glycostructure damage by Ace2-mediated feedback regulation of Cek1 signaling
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DOI：
10.1111/mmi.13494
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发表时间：
2016-12-01
影响因子：
3.6
通讯作者：
Ernst, Joachim F.
中科院分区：
文献类型：
--
作者：
van Wijlick, Lasse;Swidergall, Marc;Ernst, Joachim F.
白色念珠菌使用Cek 1 MAPK途径来修复细胞壁糖结构的损伤。蛋白质N-或O-糖基化缺陷激活Cek 1和转录因子Ace 2作为其下游靶标，以上调编码蛋白质O-甘露糖基转移酶（Pmt蛋白）的基因。在未应激的细胞中，Cek 1-Ace 2活性阻断PMT 1的表达，PMT 1被衣霉素去抑制。Ace 2的基因组结合靶点包括ZCF 21，其被Ace 2上调，并发现在未应激的细胞中抑制PMT 1转录。令人惊讶的是，编码Cek 1途径组分的基因，包括MSB 2、CST 20、HST 7、CEK 1和ACE 2，也被鉴定为Ace 2靶标，表明在N-糖基化应激下Ace 2介导的途径基因的转录扩增。在此条件下，检测到Ace 2蛋白与上游MAPKKK Cst 20的物理相互作用。Cst 20-GFP显示应激诱导的从细胞质输入到细胞核和Ace 2的磷酸化。有趣的是，Cst 20的强制核定位抑制Cek 1-Ace 2信号传导，而Cst 20的强制胞质定位保留完整的信号传导活性，表明核Cst 20下调Cek 1通路。总之，这些结果表明Ace 2是一个多功能的转录调节因子，它激活C. Cek 1信号通过正向和负反馈调节。
Candida albicans uses the Cek1 MAPK pathway to restore cells from damage of its cell wall glycostructures. Defective protein N- or O-glycosylation activates Cek1 and the transcription factor Ace2 as its downstream target, to upregulate genes encoding protein O-mannosyltransferases (Pmt proteins). In unstressed cells, Cek1-Ace2 activity blocks expression of PMT1, which is de-repressed by tunicamycin. Genomic binding targets of Ace2 included ZCF21, which was upregulated by Ace2 and found to repress PMT1 transcription in unstressed cells. Surprisingly, genes encoding components of the Cek1 pathway including MSB2, CST20, HST7, CEK1 and ACE2 were also identified as Ace2 targets indicating Ace2-mediated transcriptional amplification of pathway genes under N-glycosylation stress. In this condition, physical interaction of the Ace2 protein with the upstream MAPKKK Cst20 was detected. Cst20-GFP showed stress-induced import from the cytoplasm into the nucleus and phosphorylation of Ace2. Interestingly, forced nuclear localization of Cst20 inhibited Cek1-Ace2 signaling, while forced cytoplasmic localization of Cst20 retained full signaling activity, suggesting that nuclear Cst20 downregulates the Cek1 pathway. Collectively, the results indicate that Ace2 is a versatile multifunctional transcriptional regulator, which activates glycostress responses of C. albicans by both positive forward and negative feedback regulation of Cek1 signaling.