School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Biochem Biophys Res Commun. 2019 Oct 1;517(4):755-761. doi: 10.1016/j.bbrc.2019.07.128. Epub 2019 Aug 8.
Ras proteins are highly conserved small GTPases in eukaryotes. GTP-bound Ras binds to effectors to trigger signaling cascades. In order to understand how extensive is the functional homology between the highly homologous proteins, S. cerevisiae Ras2 and C. albicans Ras1, we examined whether ScRas2 could functionally complement CaRas1 in activating hyphal morphogenesis as well as GPI anchor biosynthesis. We show that ScRas2 functionally complements CaRas1 in rescuing growth as well as activating hyphal growth, a process that involves plasma membrane localized Ras activating cAMP/PKA signaling via Cyr1. However, ScRas2 is unable to activate the GPI-N-acetylglucosaminyl transferase (GPI-GnT) which catalyzes the first step of GPI biosynthesis. That CaRas1 alone activates GPI-GnT and not ScRas2 suggests that this process is cAMP independent. Interestingly, CaRas1 transcriptionally activates CaGPI2, encoding a GPI-GnT subunit that has been shown to interact with CaRas1 physically. In turn, CaGPI2 downregulates CaGPI19, encoding another GPI-GnT subunit. This has direct consequences for expression of CaERG11, encoding the target of azole antifungals. This effect too is specific to CaRas1 and ScRas2 is unable to replicate it.
Ras 蛋白是真核生物中高度保守的小 GTP 酶。结合 GTP 的 Ras 与效应物结合，触发信号级联。为了了解高度同源的蛋白质之间的功能同源性有多广泛，我们研究了 S. cerevisiae Ras2 和 C. albicans Ras1 是否可以在激活菌丝形态发生以及 GPI 锚生物合成方面发挥功能互补作用。我们表明，ScRas2 可以在挽救生长以及激活菌丝生长方面对 CaRas1 进行功能互补，这一过程涉及通过 Cyr1 定位于质膜的 Ras 激活 cAMP/PKA 信号传导。然而，ScRas2 无法激活 GPI-N-乙酰葡萄糖胺转移酶（GPI-GnT），该酶催化 GPI 生物合成的第一步。CaRas1 单独激活 GPI-GnT 而不是 ScRas2 表明该过程不依赖于 cAMP。有趣的是，CaRas1 转录激活编码 GPI-GnT 亚基的 CaGPI2，该亚基已被证明与 CaRas1 物理相互作用。反过来，CaGPI2 下调编码另一个 GPI-GnT 亚基的 CaGPI19。这对编码唑类抗真菌药物靶标的 CaERG11 的表达有直接影响。这种影响也是 CaRas1 特有的，ScRas2 无法复制。
