School of Biosciences, University of Exeter, Geoffrey Pope Building, Exeter EX4 4QD, UK.
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
J Cell Sci. 2021 Dec 15;134(24). doi: 10.1242/jcs.258889. Epub 2021 Dec 16.
Echinocandins such as caspofungin are frontline antifungal drugs that compromise β-1,3 glucan synthesis in the cell wall. Recent reports have shown that fungal cells can resist killing by caspofungin by upregulation of chitin synthesis, thereby sustaining cell wall integrity (CWI). When echinocandins are removed, the chitin content of cells quickly returns to basal levels, suggesting that there is a fitness cost associated with having elevated levels of chitin in the cell wall. We show here that simultaneous activation of the calcineurin and CWI pathways generates a subpopulation of Candida albicans yeast cells that have supra-normal chitin levels interspersed throughout the inner and outer cell wall, and that these cells are non-viable, perhaps due to loss of wall elasticity required for cell expansion and growth. Mutations in the Ca2+-calcineurin pathway prevented the formation of these non-viable supra-high chitin cells by negatively regulating chitin synthesis driven by the CWI pathway. The Ca2+-calcineurin pathway may therefore act as an attenuator that prevents the overproduction of chitin by coordinating both chitin upregulation and negative regulation of the CWI signaling pathway. This article has an associated First Person interview with the first author of the paper.
棘白菌素类药物（如卡泊芬净）是一线抗真菌药物，可破坏细胞壁中的β-1,3 葡聚糖合成。最近的报告表明，真菌细胞可以通过上调几丁质合成来抵抗卡泊芬净的杀伤作用，从而维持细胞壁完整性（CWI）。当去除棘白菌素类药物时，细胞中的几丁质含量迅速恢复到基础水平，这表明细胞壁中几丁质水平升高与适应度成本有关。我们在这里表明，钙调神经磷酸酶和 CWI 途径的同时激活会产生一种白色念珠菌酵母细胞的亚群，这些细胞的内、外壁中都有超高水平的几丁质，而且这些细胞是不可存活的，可能是由于失去了细胞扩张和生长所需的细胞壁弹性。钙调神经磷酸酶途径中的突变通过负调控由 CWI 途径驱动的几丁质合成，阻止了这些不可存活的超高几丁质细胞的形成。因此，钙调神经磷酸酶途径可能作为一种衰减器，通过协调几丁质的上调和 CWI 信号通路的负调控，来防止几丁质的过度产生。本文有一篇对该论文第一作者的相关第一人称采访。
