A single nucleotide polymorphism uncovers a novel function for the transcription factor Ace2 during Candida albicans hyphal development.
A single nucleotide polymorphism uncovers a novel function for the transcription factor Ace2 during Candida albicans hyphal development.
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DOI：
10.1371/journal.pgen.1005152
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发表时间：
2015-04
期刊：
影响因子：
4.5
通讯作者：
de Aldana CR
中科院分区：
文献类型：
--
作者：
Calderón-Noreña DM;González-Novo A;Orellana-Muñoz S;Gutiérrez-Escribano P;Arnáiz-Pita Y;Dueñas-Santero E;Suárez MB;Bougnoux ME;Del Rey F;Sherlock G;d'Enfert C;Correa-Bordes J;de Aldana CR
Candida albicans is a major invasive fungal pathogen in humans. An important virulence factor is its ability to switch between the yeast and hyphal forms, and these filamentous forms are important in tissue penetration and invasion. A common feature for filamentous growth is the ability to inhibit cell separation after cytokinesis, although it is poorly understood how this process is regulated developmentally. In C. albicans, the formation of filaments during hyphal growth requires changes in septin ring dynamics. In this work, we studied the functional relationship between septins and the transcription factor Ace2, which controls the expression of enzymes that catalyze septum degradation. We found that alternative translation initiation produces two Ace2 isoforms. While full-length Ace2, Ace2L, influences septin dynamics in a transcription-independent manner in hyphal cells but not in yeast cells, the use of methionine-55 as the initiation codon gives rise to Ace2S, which functions as the nuclear transcription factor required for the expression of cell separation genes. Genetic evidence indicates that Ace2L influences the incorporation of the Sep7 septin to hyphal septin rings in order to avoid inappropriate activation of cell separation during filamentous growth. Interestingly, a natural single nucleotide polymorphism (SNP) present in the C. albicans WO-1 background and other C. albicans commensal and clinical isolates generates a stop codon in the ninth codon of Ace2L that mimics the phenotype of cells lacking Ace2L. Finally, we report that Ace2L and Ace2S interact with the NDR kinase Cbk1 and that impairing activity of this kinase results in a defect in septin dynamics similar to that of hyphal cells lacking Ace2L. Together, our findings identify Ace2L and the NDR kinase Cbk1 as new elements of the signaling system that modify septin ring dynamics in hyphae to allow cell-chain formation, a feature that appears to have evolved in specific C. albicans lineages. Candida albicans is a major fungal pathogen in immunologically compromised patients. A key virulence trait is its ability to switch between the yeast and hyphal forms. Whereas yeast cells are required for dissemination, the filamentous forms are important in tissue penetration and invasion. In order to make a hypha, cell separation must be inhibited after cytokinesis, although the full extent of its regulation remains unknown. Previously, we have shown that the inhibition of cell separation in hyphae requires a modification of the dynamic properties of septins, a conserved family of GTPases that normally form a ring at the site of cytokinesis. Here we describe new factors regulating septin dynamics during hyphal development. We have discovered that an alternative translation initiation of ACE2 mRNAs gives rise to an Ace2 protein, Ace2L, with an extra 54 aa at the N-terminus that exhibits a localization and function different from Ace2 transcription factor. This Ace2L protein is upregulated upon hyphal induction and regulates the incorporation of the Sep7 septin into the septin rings to avoid inappropriate activation of cell separation in hyphae. Finally, we present evidence suggesting that the NDR kinase Cbk1 interacts with Ace2L to regulate this process.
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