Mendelsohn Sigal, Pinsky Mariel, Weissman Ziva, Kornitzer Daniel
Department of Molecular Microbiology, B. Rappaport Faculty of Medicine, Technion-I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
mSphere. 2017 Mar 8;2(2). doi: 10.1128/mSphere.00248-16. eCollection 2017 Mar-Apr.
The ability to switch between proliferation as yeast cells and development into hyphae is a hallmark of . The switch to hyphal morphogenesis depends on external inducing conditions, but its efficiency is augmented in stationary-phase cells. Ume6, a transcription factor that is itself transcriptionally induced under hypha-promoting conditions, is both necessary and sufficient for hyphal morphogenesis. We found that Ume6 is regulated posttranslationally by the cell cycle kinase Cdc28/Cdk1, which reduces Ume6 activity via different mechanisms using different cyclins. Together with the cyclin Hgc1, Cdk1 promotes degradation of Ume6 via the SCF ubiquitin ligase. Since is a key transcriptional target of Ume6, this results in a negative-feedback loop between Hgc1 and Ume6. In addition, we found that Cln3, a G cyclin that is essential for cell cycle progression and yeast proliferation, suppresses hyphal morphogenesis and that Cln3 suppresses Ume6 activity both in the heterologous system and in itself. This activity of Cln3 may provide the basis for the antagonistic relationship between yeast proliferation and hyphal development in . The yeast to hypha (mold) morphogenetic switch of plays a role in its virulence and constitutes a diagnostic trait for this organism, the most prevalent systemic fungal pathogen in industrialized countries. It has long been known that hyphae are most efficiently induced from stationary cultures. Here, a molecular basis for this observation is provided. The G cyclin Cln3, an essential promoter of yeast proliferation, was found to suppress hyphal induction. Suppression of hyphal induction is achieved by inhibition of the activity of the central activator of hyphal morphogenesis, the transcription factor Ume6. Thus, levels of Cln3 control the switch between proliferation of as individual yeast cells and development into extended hyphae, a switch that may preface the proliferation/differentiation switch in multicellular organisms.
在作为酵母细胞进行增殖和发育成菌丝之间进行转换的能力是……的一个标志。向菌丝形态发生的转换取决于外部诱导条件，但其效率在稳定期细胞中会增强。Ume6是一种转录因子，其本身在促进菌丝生长的条件下被转录诱导，对于菌丝形态发生既必要又充分。我们发现Ume6在翻译后受到细胞周期激酶Cdc28/Cdk1的调控，Cdc28/Cdk1通过使用不同的细胞周期蛋白的不同机制降低Ume6的活性。与细胞周期蛋白Hgc1一起，Cdk1通过SCF泛素连接酶促进Ume6的降解。由于……是Ume6的关键转录靶点，这导致了Hgc1和Ume6之间的负反馈环。此外，我们发现Cln3，一种对细胞周期进程和酵母增殖至关重要的G细胞周期蛋白，抑制菌丝形态发生，并且Cln3在异源……系统以及在……自身中均抑制Ume6的活性。Cln3的这种活性可能为……中酵母增殖和菌丝发育之间的拮抗关系提供基础。……从酵母到菌丝（霉菌）的形态发生转换在其毒力中起作用，并构成该生物体（工业化国家中最普遍的系统性真菌病原体）的一个诊断特征。长期以来已知从静止培养物中能最有效地诱导出菌丝。在此，提供了这一观察结果的分子基础。G细胞周期蛋白Cln3，酵母增殖的一个必需促进因子，被发现抑制菌丝诱导。通过抑制菌丝形态发生的核心激活因子转录因子Ume6的活性来实现对菌丝诱导的抑制。因此，Cln3的水平控制着……作为单个酵母细胞进行增殖和发育成延长菌丝之间的转换，这一转换可能是多细胞生物体中增殖/分化转换的前奏。
