Abnormal sterols disrupt cellular functions through yet unclear mechanisms. In Saccharomyces cerevisiae, accumulation of Δ8-sterols, the same type of sterols observed in patients of Conradi–Hünermann–Happle syndrome or in fungi after amine fungicide treatment, leads to cell wall weakness. We have studied the influence of Δ8-sterols on the activity of glucan synthase I, the protein synthetizing the main polymer in fungal cell walls, its regulation by the Cell Wall Integrity (CWI) pathway, and its transport from the endoplasmic reticulum to the plasma membrane. We ascertained that the catalytic characteristics were mostly unaffected by the presence of abnormal sterols but the enzyme was partially retained in the endoplasmic reticulum, leading to glucan deficit at the cell wall. Furthermore, we observed that glucan synthase I traveled through an unconventional exocytic route to the plasma membrane that is associated with low density intracellular membranes. Also, we found out that the CWI pathway remained inactive despite low glucan levels at the cell wall. Taken together, these data suggest that Δ8-sterols affect cell walls by inhibiting unconventional secretion of proteins leading to retention and degradation of glucan synthase I, while the compensatory CWI pathway is unable to activate. These results could be instrumental to understand defects of bone development in cholesterol biosynthesis disorders and fungicide mechanisms of action.

中文翻译：

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酵母中甾醇异常诱导的细胞壁葡聚糖缺乏是由于葡聚糖合酶向质膜的转运受损所致


异常甾醇通过尚不清楚的机制破坏细胞功能。在酿酒酵母中，Δ8-甾醇的积累（在 Conradi-Hünermann-Happle 综合征患者中或在胺类杀菌剂处理后的真菌中观察到的相同类型的甾醇）会导致细胞壁衰弱。我们研究了 Δ8-甾醇对葡聚糖合成酶 I 活性的影响，葡聚糖合成酶 I 是合成真菌细胞壁中主要聚合物的蛋白质，其通过细胞壁完整性 (CWI) 途径的调节，及其从内质网到血浆的转运膜。我们确定催化特性基本上不受异常甾醇存在的影响，但酶部分保留在内质网中，导致细胞壁葡聚糖缺乏。此外，我们观察到葡聚糖合酶 I 通过非常规的胞吐途径到达与低密度细胞内膜相关的质膜。此外，我们发现尽管细胞壁的葡聚糖水平较低，CWI 途径仍然不活跃。综上所述，这些数据表明，Δ8-甾醇通过抑制蛋白质的非常规分泌来影响细胞壁，从而导致葡聚糖合酶 I 的保留和降解，而补偿性 CWI 途径无法激活。这些结果可能有助于了解胆固醇生物合成障碍中的骨发育缺陷和杀菌剂的作用机制。