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首页> 外文期刊>MBio >Phosphoregulation of Nap1 Plays a Role in Septin Ring Dynamics and Morphogenesis in Candida albicans
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Phosphoregulation of Nap1 Plays a Role in Septin Ring Dynamics and Morphogenesis in Candida albicans

机译：Nap1的磷酸化在白色念珠菌的Septin环动力学和形态发生中起作用。

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Nap1 has long been identified as a potential septin regulator in yeasts. However, its function and regulation remain poorly defined. Here, we report functional characterization of Nap1 in the human-pathogenic fungus Candida albicans. We find that deletion of NAP1 causes constitutive filamentous growth and changes of septin dynamics. We present evidence that Nap1’s cellular localization and function are regulated by phosphorylation. Phos-tag gel electrophoresis revealed that Nap1 phosphorylation is cell cycle dependent, exhibiting the lowest level around the time of bud emergence. Mass spectrometry identified 10 phosphoserine and phosphothreonine residues in a cluster near the N terminus, and mutation of these residues affected Nap1’s localization to the septin ring and cellular function. Nap1 phosphorylation involves two septin ring-associated kinases, Cla4 and Gin4, and its dephosphorylation occurs at the septin ring in a manner dependent on the phosphatases PP2A and Cdc14. Furthermore, the nap1Δ/Δ mutant and alleles carrying mutations of the phosphorylation sites exhibited greatly reduced virulence in a mouse model of systemic candidiasis. Together, our findings not only provide new mechanistic insights into Nap1’s function and regulation but also suggest the potential to target Nap1 in future therapeutic design. >IMPORTANCE Septins are conserved filament-forming GTPases involved in a wide range of cellular events, such as cytokinesis, exocytosis, and morphogenesis. In Candida?albicans, the most prevalent human fungal pathogen, septin functions are indispensable for its virulence. However, the molecular mechanisms by which septin structures are regulated are poorly understood. In this study, we deleted NAP1, a gene encoding a putative septin regulator, in C.?albicans and found that cells lacking NAP1 showed abnormalities in morphology, invasive growth, and septin ring dynamics. We identified a conserved N-terminal phosphorylation cluster on Nap1 and demonstrated that phosphorylation at these sites regulates Nap1 localization and function. Importantly, deletion of NAP1 or mutation in the N-terminal phosphorylation cluster strongly reduced the virulence of C.?albicans in a mouse model of systemic infection. Thus, this study not only provides mechanistic insights into septin regulation but also suggests Nap1 as a potential antifungal target.
机译：Nap1长期以来一直被认为是酵母中潜在的Septin调节剂。但是，它的功能和调节仍然不清楚。在这里，我们报告人致病性真菌白色念珠菌中Nap1的功能表征。我们发现， NAP1 的缺失会导致组成型丝状生长和Septin动态变化。我们提供的证据表明Nap1的细胞定位和功能受磷酸化作用调节。磷酸标记凝胶电泳显示Nap1磷酸化是细胞周期依赖性的，在芽出苗时表现出最低水平。质谱鉴定出在N末端附近的簇中有10个磷酸丝氨酸和磷酸苏氨酸残基，这些残基的突变影响了Nap1定位于Septin环和细胞功能。 Nap1磷酸化涉及两个与Septin环相关的激酶Cla4和Gin4，其去磷酸化作用在septin环上取决于磷酸酶PP2A和Cdc14。此外，在系统性念珠菌病小鼠模型中，nap1Δ/Δ突变体和携带磷酸化位点突变的等位基因表现出极大的降低的毒力。总之，我们的发现不仅为Nap1的功能和调控提供了新的机械学见解，而且还暗示了在未来的治疗设计中靶向Nap1的潜力。 >重要：Septins是一种保守的长丝形成型GTPases，涉及广泛的细胞事件，例如胞质分裂，胞吐作用和形态发生。在白色念珠菌（一种最普遍的人类真菌病原体）中，Septin功能对其毒力是必不可少的。但是，人们尚不清楚调控septin结构的分子机制。在这项研究中，我们删除了白色假丝酵母中编码假定的Septin调节剂的基因 NAP1 ，发现缺少 NAP1 的细胞显示异常在形态，侵袭性生长和Septin环动力学方面。我们在Nap1上确定了一个保守的N末端磷酸化簇，并证明在这些位点的磷酸化调节Nap1的定位和功能。重要的是，在系统感染的小鼠模型中， NAP1 的缺失或N末端磷酸化簇中的突变会大大降低 C.albicans 的毒力。因此，这项研究不仅提供了对Septin调节的机制性见解，而且还暗示了Nap1作为潜在的抗真菌靶标。

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