Department of Biochemistry, University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan, PR 00936-067.
School of Science and Technology, University Ana G. Mendez, Cupey Campus, Ana G Mendez Ave, No.1399, San Juan, PR 00926.
G3 (Bethesda). 2020 Sep 2;10(9):3121-3135. doi: 10.1534/g3.120.401468.
Antifungal drug discovery and design is very challenging because of the considerable similarities in genetic features and metabolic pathways between fungi and humans. However, cell wall composition represents a notable point of divergence. Therefore, a research strategy was designed to improve our understanding of the mechanisms for maintaining fungal cell wall integrity, and to identify potential targets for new drugs that modulate the underlying protein-protein interactions in This study defines roles for and and their interacting protein partners in the cell wall integrity signaling and cell survival mechanisms that respond to treatments with fluconazole and hydrogen peroxide. By combined genetic and biochemical approaches, we report the discovery of 12 novel protein interactors of and Of these, interacting partners and , have opposing roles in the resistance and sensitivity to fluconazole treatments respectively. The interaction of with was confirmed by iMYTH and IP-MS approaches and is shown to play a dominant role in response to oxidative stress induced by hydrogen peroxide. Consistent with an earlier study, was also identified as an interacting partner of and cell wall integrity signaling proteins. Collectively, this study expands the interaction networks of the mechanosensory proteins of the Cell Wall Integrity pathway.
抗真菌药物的发现和设计极具挑战性,因为真菌和人类在遗传特征和代谢途径方面有很多相似之处。然而,细胞壁的组成则代表了一个明显的差异点。因此,我们设计了一种研究策略,旨在增进我们对维持真菌细胞壁完整性机制的理解,并确定潜在的药物靶点,以调节潜在的蛋白质-蛋白质相互作用。这项研究定义了 和 及其相互作用蛋白伙伴在细胞壁完整性信号和细胞存活机制中的作用,这些机制对氟康唑和过氧化氢的处理有反应。通过结合遗传和生化方法,我们报告了 12 种新的 和 的蛋白相互作用因子的发现。其中,与 相互作用的伙伴 和 分别在对氟康唑治疗的耐药性和敏感性方面发挥着相反的作用。 与 的相互作用通过 iMYTH 和 IP-MS 方法得到了证实,并显示在响应过氧化氢诱导的氧化应激方面发挥着主导作用。与早期的一项研究一致, 也被鉴定为细胞壁完整性信号蛋白 和 的相互作用伙伴。总的来说,这项研究扩展了细胞壁完整性途径的机械感觉蛋白的相互作用网络。