Department of Biological Sciences, State University of New York at Buffalo, Buffalo, New York, USA.
Department of Biological Sciences, State University of New York at Buffalo, Buffalo, New York, USA
mSphere. 2021 May 5;6(3):e00053-21. doi: 10.1128/mSphere.00053-21.
is a major human fungal pathogen that encounters varied host environments during infection. In response to environmental cues, switches between ovoid yeast and elongated hyphal growth forms, and this morphological plasticity contributes to virulence. Environmental changes that alter the cell's metabolic state could be sensed by sirtuins, which are NAD-dependent deacetylases. Here, we studied the roles of three sirtuin deacetylases-Sir2, Hst1, and Hst2-in the hyphal growth of We made single, double, and triple sirtuin knockout strains and tested their ability to switch from yeast to hyphae. We found that true hypha formation was significantly reduced by the deletion of but not or Moreover, the expression of hypha-specific genes , , and decreased in the mutant compared to the wild type. This regulation of hypha formation was likely dependent on the deacetylase activity of Sir2, as a similar defect in hypha formation was observed when an asparagine known to be required for deacetylation was mutated. Finally, we found that Sir2 and Hst1 were localized to the nucleus, with Sir2 specifically focused in the nucleolus. This nuclear localization suggests a role for Sir2 and Hst1 in regulating gene expression. In contrast, Hst2 was localized to the cytoplasm. In conclusion, our results suggest that Sir2 plays a critical and nonredundant role in hyphal growth of is one of the most common causes of hospital-acquired systemic fungal infections in the United States. It can switch between ovoid yeast and elongated hyphal growth forms in response to environmental cues. This morphological transition is essential for its survival in the host. Thus, identifying regulators involved in this process can lead to new therapies. In this study, we examined the contribution of three regulators called sirtuins (Sir2, Hst1, and Hst2) to the yeast-to-hypha transition of We found that loss of Sir2 but not Hst1 or Hst2 hampered hypha formation. Moreover, the defect was caused by the loss of the catalytic activity of Sir2. Our study may lay the groundwork for discovering novel targets for antifungal therapies.
是一种主要的人类真菌病原体，在感染过程中会遇到各种宿主环境。为了应对环境线索，会在卵形酵母和伸长的菌丝生长形态之间切换，这种形态可塑性有助于毒力。改变细胞代谢状态的环境变化可以被依赖 NAD 的去乙酰化酶 sirtuins 感知。在这里，我们研究了三种 sirtuin 去乙酰化酶（Sir2、Hst1 和 Hst2）在 的菌丝生长中的作用。我们制作了单、双和三 sirtuin 缺失菌株，并测试了它们从酵母切换到菌丝的能力。我们发现，真菌丝的形成显著减少了 的缺失，但 或 缺失不会。此外，与野生型相比，菌丝特异性基因 、 和 的表达在 突变体中降低。这种菌丝形成的调节可能依赖于 Sir2 的去乙酰化酶活性，因为当需要去乙酰化的天冬酰胺发生突变时，观察到类似的菌丝形成缺陷。最后，我们发现 Sir2 和 Hst1 定位于细胞核，Sir2 特异性地聚焦在核仁中。这种核定位表明 Sir2 和 Hst1 在调节基因表达中起作用。相比之下，Hst2 定位于细胞质。总之，我们的结果表明 Sir2 在 的菌丝生长中发挥着关键的、不可替代的作用。是美国最常见的医院获得性系统性真菌感染的病原体之一。它可以根据环境线索在卵形酵母和伸长的菌丝生长形态之间切换。这种形态转变对于它在宿主中的生存至关重要。因此，确定参与这一过程的调节剂可以导致新的治疗方法。在这项研究中，我们检查了三种调节剂（Sir2、Hst1 和 Hst2）对 的酵母到菌丝转变的贡献。我们发现，Sir2 的缺失而不是 Hst1 或 Hst2 阻碍了菌丝的形成。此外，缺陷是由 Sir2 的催化活性丧失引起的。我们的研究可能为发现新型抗真菌治疗靶点奠定基础。
