The unfolded protein response (UPR), crucial for the maintenance of endoplasmic reticulum (ER) homeostasis, is tied to the regulation of multiple cellular processes in pathogenic fungi. Here, we show that Candida albicans relies on an ER‐resident protein, inositol‐requiring enzyme 1 (Ire1) for sensing ER stress and activating the UPR. Compromised Ire1 function impacts cellular processes that are dependent on functional secretory homeostasis, as inferred from transcriptional profiling. Concordantly, an Ire1‐mutant strain exhibits pleiotropic roles in ER stress response, antifungal tolerance, cell wall regulation and virulence‐related traits. Hac1 is the downstream target of C. albicans Ire1 as it initiates the unconventional splicing of the 19 bp intron from HAC1 mRNA during tunicamycin‐induced ER stress. Ire1 also activates the UPR in response to perturbations in cell wall integrity and cell membrane homeostasis in a manner that does not necessitate the splicing of HAC1 mRNA. Furthermore, the Ire1‐mutant strain is severely defective in hyphal morphogenesis and biofilm formation as well as in establishing a successful infection in vivo. Together, these findings demonstrate that C. albicans Ire1 functions to regulate traits that are essential for virulence and suggest its importance in responding to multiple stresses, thus integrating various stress signals to maintain ER homeostasis.

中文翻译：

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蛋白激酶Ire1通过调节对内质网应激的稳态适应来影响白色念珠菌的致病性

未折叠蛋白反应 (UPR) 对维持内质网 (ER) 稳态至关重要，它与病原真菌中多个细胞过程的调节有关。在这里，我们表明白色念珠菌依赖于 ER 驻留蛋白、肌醇需要酶 1 (Ire1) 来感知 ER 压力和激活 UPR。受损的 Ire1 功能会影响依赖于功能性分泌稳态的细胞过程，如从转录谱中推断的那样。一致地，Ire1 突变菌株在 ER 应激反应、抗真菌耐受性、细胞壁调节和毒力相关性状中表现出多效性。Hac1 是白色念珠菌Ire1的下游目标，因为它启动了 HAC1 的 19 bp 内含子的非常规剪接衣霉素诱导的 ER 应激过程中的 mRNA。Ire1 还以不需要剪接HAC1 mRNA的方式激活 UPR，以响应细胞壁完整性和细胞膜稳态的扰动。此外，Ire1 突变菌株在菌丝形态发生和生物膜形成以及在体内建立成功感染方面存在严重缺陷。总之，这些发现表明白色念珠菌Ire1 可调节对毒力至关重要的性状，并表明其在应对多种压力方面的重要性，从而整合各种压力信号以维持 ER 稳态。