Arrestins, a structurally specialized and functionally diverse group of proteins, are central regulators of adaptive cellular responses in eukaryotes. Previous studies on fungal arrestins have demonstrated their capacity to modulate diverse cellular processes through their adaptor functions, facilitating the localization and function of other proteins. However, the mechanisms by which arrestin-regulated processes are involved in fungal virulence remain unexplored. We have identified a small family of four arrestins, Ali1, Ali2, Ali3, and Ali4, in the human fungal pathogen Cryptococcus neoformans Using complementary microscopy, proteomic, and reverse genetics techniques, we have defined a role for Ali1 as a novel contributor to cytokinesis, a fundamental cell cycle-associated process. We observed that Ali1 strongly interacts with proteins involved in lipid synthesis, and that ali1Δ mutant phenotypes are rescued by supplementation with lipid precursors that are used to build cellular membranes. From these data, we hypothesize that Ali1 contributes to cytokinesis by serving as an adaptor protein, facilitating the localization of enzymes that modify the plasma membrane during cell division, specifically the fatty acid synthases Fas1 and Fas2. Finally, we assessed the contributions of the C. neoformans arrestin family to virulence to better understand the mechanisms by which arrestin-regulated adaptive cellular responses influence fungal infection. We observed that the C. neoformans arrestin family contributes to virulence, and that the individual arrestin proteins likely fulfill distinct functions that are important for disease progression.IMPORTANCE To survive under unpredictable conditions, all organisms must adapt to stressors by regulating adaptive cellular responses. Arrestin proteins are conserved regulators of adaptive cellular responses in eukaryotes. Studies that have been limited to mammals and model fungi have demonstrated that the disruption of arrestin-regulated pathways is detrimental for viability. The human fungal pathogen Cryptococcus neoformans causes more than 180,000 infection-related deaths annually, especially among immunocompromised patients. In addition to being genetically tractable, C. neoformans has a small arrestin family of four members, lending itself to a comprehensive characterization of its arrestin family. This study serves as a functional analysis of arrestins in a pathogen, particularly in the context of fungal fitness and virulence. We investigate the functions of one arrestin protein, Ali1, and define its novel contributions to cytokinesis. We additionally explore the virulence contributions of the C. neoformans arrestin family and find that they contribute to disease establishment and progression.

中文翻译：

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真菌抑制蛋白有助于细胞周期进程和发病机理。

Arrestins是结构上专门且功能多样的蛋白质组，是真核生物中适应性细胞反应的主要调节剂。以前关于真菌抑制蛋白的研究已经证明了它们通过其衔接子功能调节多种细胞过程的能力，从而促进了其他蛋白质的定位和功能。然而，仍未探索使抑制素调节的过程参与真菌毒力的机制。我们在人类真菌病原体新隐球菌中鉴定出一个由四个抑制蛋白组成的小家族，分别为Ali1，Ali2，Ali3和Ali4。 ，这是与细胞周期相关的基本过程。我们观察到Ali1与参与脂质合成的蛋白质发生强烈相互作用，并且通过补充用于构建细胞膜的脂质前体来拯救ali1Δ突变表型。从这些数据，我们假设Ali1通过充当衔接蛋白，促进细胞分裂过程中修饰质膜的酶（特别是脂肪酸合酶Fas1和Fas2）的定位而有助于胞质分裂。最后，我们评估了新孢梭菌抑制蛋白家族对毒力的贡献，以更好地了解抑制蛋白调节的适应性细胞反应影响真菌感染的机制。我们观察到新孢梭菌抑制素家族有助于增加毒力，重要提示为了在无法预测的条件下生存，所有生物都必须通过调节适应性细胞反应来适应应激源。抑制蛋白是真核生物中适应性细胞反应的保守调节剂。仅限于哺乳动物和模型真菌的研究表明，restarin调节的通路的破坏对生存能力有害。人类真菌病原体新隐球菌每年导致超过18万例与感染相关的死亡，尤其是在免疫功能低下的患者中。除了在遗传上易于治疗外，新孢子虫还具有一个由四个成员组成的小型逮捕蛋白家族，这使其具有其逮捕蛋白家族的全面特征。这项研究可作为病原体中抑制素的功能分析，尤其是在真菌适应性和毒性方面。我们调查一种抑制蛋白Ali1的功能，并定义其对胞质分裂的新贡献。我们还探讨了新孢梭菌抑制蛋白家族的毒性贡献，发现它们有助于疾病的建立和发展。