酿酒酵母应对镉胁迫的分子机理研究
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摘要
镉离子(Cd~(2+))作为人体的非必需金属离子，具有致癌性，对人类健康造成严重威胁，但其作用靶点及毒性机理尚不完全明确。本文在实验室前期工作的基础上，对112个对Cd~(2+)敏感的酿酒酵母基因缺失株进行了初步的系统研究。发现其中81个基因缺失株对必需金属离子Mn~(2+), Zn~(2+)或Fe~(2+)的胁迫也敏感，而其它31个基因缺失株对Cd~(2+)胁迫具有专一性。这些基因的功能主要集中在蛋白修饰、转录、信号传导和细胞运输等方面。
通过倍比稀释表型分析和蛋白印迹检测发现，两个MAP Kinase信号传导途径，细胞壁完整性途径(CWI)和高渗透压途径(HOG)，参与Cd~(2+)胁迫的细胞应答。HOG途径中Sho1和Sln1分支都参与了Cd~(2+)胁迫下Hog1p的激活。在CWI途径中，Cd~(2+)激活Slt2p是通过膜感受器Mid2p将信号通过GEFs-Rom1p传递到Rho1，进而激活PKC途径中的MAP Kinase.此外，Slt2p的激活还依赖TOR途径中的Sit4，但与HOG途径无关。酵母细胞在Cd~(2+)胁迫下Hog1p和Slt2p的激活与细胞内钙离子浓度变化无关。但是，Cd~(2+)胁迫不导致Hog1和Slt2细胞内的移位。此外，培养基中加入Mn~(2+)或Fe~(2+)都可以抑制hog1Δ和slt2Δ对Cd~(2+)的敏感性，表明Mn~(2+)或Fe~(2+)的缺陷导致细胞对Cd~(2+)的敏感性。而Mn~(2+)通道蛋白Smf1&Smf2和Fe~(2+)通道蛋白Fet4缺失导致细胞对Cd~(2+)的耐受性，说明Cd~(2+)可能借助Mn~(2+)通道和Fe~(2+)通道进入细胞。Hog1和Slt2正向调控SMF1, SMF2和PCA1基因的转录。
与细胞运输相关的VPS家族基因中有29个基因缺失后对Cd~(2+)表现出生长缺陷，其中包括9个与蛋白降解相关的VPS Class E家族基因。文献报道锌通道Zrt1介导Cd~(2+)进入细胞，但zrt1菌株在Cd~(2+)胁迫下的表型与野生型一致。ZRT1/2与VPS Class E的双基因缺失菌株对Cd~(2+)的表型与VPS Class E基因单独缺失时一致。蛋白印迹检测发现Cd~(2+)胁迫下Zrt1p的降解方式与Zn~(2+)胁迫一致，需要VPSClass E的参与。
Cadmium ions are not essential for eukarytic cells, but could induce cancers andare toxic to human health. Our lab previously identified112cadmium-sensitive genemutations. In this study, we find that81of these mutants are also sensitive tomanganese, zinc and iron divalent ions, but the rest31are not and only specificallysensitive to cadmium ions. Main functions of these genes are involved in protein fate,transcriptional regulation, cellular communication, signal transduction, and cellulartransport.
Through serial dilution assay and Western blot analysis, we have identified twomitogen-activate protein (MAP) kinase signaling pathways, the cell wall integrity(CWI) pathway and high-osmolarity and glycerol (HOG) pathway, are involved in theresponse to cadmium stress. Cadmium stress activates Hog1through two independentupstream branches, Sho1and Sln1. Slt2phosphorylation dependes on the CWIpathway sensor Mid2, which activates the Rom1GEFs. The sensor stimulatednucleotide exchange on Rho1, which then activates the PKC pathway. In addition,phosphorylation of Slt2depends on Sit4, one of the elements in the target ofrapamycin (TOR) pathway, but does not require the HOG pathway. In response tocadmium stress, subcellular localization of Slt2and Hog1is not affected.
Supplementation of1mM Mn~(2+)or10mM Fe~(2+)in media suppresses the cadmiumsensitivity of hog1Δ and slt2Δ cells, suggesting that manganese or iron deficiency isan important determinant of cadmium toxicity. In line with this, transporter smf1Δ,smf2Δ and fet4Δ mutants exhibit cadmium tolerance. Transcriptional expression ofSMF1, SMF2and PCA1are positively regulated by Hog1and Slt2. SMF1and SMF2promoter sequences have Swi6and Smp1transcription factor binding sites.
VPS genes for nine cadmium-sensitive mutants participate in theubiquitin-dependent sorting of transmembrane proteins at the endosome. Zrt1is oneof the major pathways through which Cd~(2+)enters yeast, but the zrt1Δ mutant is notsensitive to cadmium stress. Deletion of ZRT1or ZRT2does not affect the cadmiumsensitivity of VPS Class E gene mutations. Western blot analysis suggested that Zrt1degradation requires the VPS Class E family in response to cadmium stress.
通过倍比稀释表型分析和蛋白印迹检测发现，两个MAP Kinase信号传导途径，细胞壁完整性途径(CWI)和高渗透压途径(HOG)，参与Cd~(2+)胁迫的细胞应答。HOG途径中Sho1和Sln1分支都参与了Cd~(2+)胁迫下Hog1p的激活。在CWI途径中，Cd~(2+)激活Slt2p是通过膜感受器Mid2p将信号通过GEFs-Rom1p传递到Rho1，进而激活PKC途径中的MAP Kinase.此外，Slt2p的激活还依赖TOR途径中的Sit4，但与HOG途径无关。酵母细胞在Cd~(2+)胁迫下Hog1p和Slt2p的激活与细胞内钙离子浓度变化无关。但是，Cd~(2+)胁迫不导致Hog1和Slt2细胞内的移位。此外，培养基中加入Mn~(2+)或Fe~(2+)都可以抑制hog1Δ和slt2Δ对Cd~(2+)的敏感性，表明Mn~(2+)或Fe~(2+)的缺陷导致细胞对Cd~(2+)的敏感性。而Mn~(2+)通道蛋白Smf1&Smf2和Fe~(2+)通道蛋白Fet4缺失导致细胞对Cd~(2+)的耐受性，说明Cd~(2+)可能借助Mn~(2+)通道和Fe~(2+)通道进入细胞。Hog1和Slt2正向调控SMF1, SMF2和PCA1基因的转录。
与细胞运输相关的VPS家族基因中有29个基因缺失后对Cd~(2+)表现出生长缺陷，其中包括9个与蛋白降解相关的VPS Class E家族基因。文献报道锌通道Zrt1介导Cd~(2+)进入细胞，但zrt1菌株在Cd~(2+)胁迫下的表型与野生型一致。ZRT1/2与VPS Class E的双基因缺失菌株对Cd~(2+)的表型与VPS Class E基因单独缺失时一致。蛋白印迹检测发现Cd~(2+)胁迫下Zrt1p的降解方式与Zn~(2+)胁迫一致，需要VPSClass E的参与。
Cadmium ions are not essential for eukarytic cells, but could induce cancers andare toxic to human health. Our lab previously identified112cadmium-sensitive genemutations. In this study, we find that81of these mutants are also sensitive tomanganese, zinc and iron divalent ions, but the rest31are not and only specificallysensitive to cadmium ions. Main functions of these genes are involved in protein fate,transcriptional regulation, cellular communication, signal transduction, and cellulartransport.
Through serial dilution assay and Western blot analysis, we have identified twomitogen-activate protein (MAP) kinase signaling pathways, the cell wall integrity(CWI) pathway and high-osmolarity and glycerol (HOG) pathway, are involved in theresponse to cadmium stress. Cadmium stress activates Hog1through two independentupstream branches, Sho1and Sln1. Slt2phosphorylation dependes on the CWIpathway sensor Mid2, which activates the Rom1GEFs. The sensor stimulatednucleotide exchange on Rho1, which then activates the PKC pathway. In addition,phosphorylation of Slt2depends on Sit4, one of the elements in the target ofrapamycin (TOR) pathway, but does not require the HOG pathway. In response tocadmium stress, subcellular localization of Slt2and Hog1is not affected.
Supplementation of1mM Mn~(2+)or10mM Fe~(2+)in media suppresses the cadmiumsensitivity of hog1Δ and slt2Δ cells, suggesting that manganese or iron deficiency isan important determinant of cadmium toxicity. In line with this, transporter smf1Δ,smf2Δ and fet4Δ mutants exhibit cadmium tolerance. Transcriptional expression ofSMF1, SMF2and PCA1are positively regulated by Hog1and Slt2. SMF1and SMF2promoter sequences have Swi6and Smp1transcription factor binding sites.
VPS genes for nine cadmium-sensitive mutants participate in theubiquitin-dependent sorting of transmembrane proteins at the endosome. Zrt1is oneof the major pathways through which Cd~(2+)enters yeast, but the zrt1Δ mutant is notsensitive to cadmium stress. Deletion of ZRT1or ZRT2does not affect the cadmiumsensitivity of VPS Class E gene mutations. Western blot analysis suggested that Zrt1degradation requires the VPS Class E family in response to cadmium stress.
引文
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