Many species of pathogenic fungi deploy the unfolded protein response (UPR) to expand the folding capacity of the endoplasmic reticulum (ER) in proportion to the demand for virulence-related proteins that traffic through the secretory pathway. Although Ca²⁺ plays a pivotal role in ER function, the mechanism by which transcriptional upregulation of the protein folding machinery is coordinated with Ca²⁺ homeostasis is incompletely understood. In this study, we investigated the link between the UPR and genes encoding P-type Ca²⁺-ATPases in the human-pathogenic mold Aspergillus fumigatus. We demonstrate that acute ER stress increases transcription of the srcA gene, encoding a member of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) family, as well as that of pmrA, encoding a secretory pathway Ca²⁺-ATPase (SPCA) in the Golgi membrane. Loss of the UPR transcription factor HacA prevented the induction of srcA and pmrA transcription during ER stress, defining these ER/Golgi Ca²⁺ pumps as novel downstream targets of this pathway. While deletion of srcA alone caused no major deficiencies, a ΔsrcA/ΔpmrA mutant displayed a severe polarity defect, was hypersensitive to ER stress, and showed attenuated virulence. In addition, cell wall analyses revealed a striking reduction in mannose levels in the absence of both Ca²⁺ pumps. The ΔhacA mutant was hypersensitive to agents that block calcineurin-dependent signaling, consistent with a functional coupling between the UPR and Ca²⁺ homeostasis. Together, these findings demonstrate that the UPR integrates the need for increased levels of chaperone and folding enzymes with an influx of Ca²⁺ into the secretory pathway to support fungal growth, stress adaptation, and pathogenicity.

中文翻译：

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展开的蛋白质反应与内质网/高尔基Ca2 + -ATPases之间的功能性耦合促进了烟曲霉的胁迫耐受性，细胞壁生物合成和毒力。

许多种类的致病真菌会根据与通过分泌途径运输的毒力相关蛋白的需求成比例地展开蛋白折叠反应（UPR），以扩大内质网（ER）的折叠能力。尽管Ca ²⁺在ER功能中起着关键作用，但对蛋白质折叠机制的转录上调与Ca ²⁺稳态协调的机制尚不完全清楚。在这项研究中，我们调查了UPR和人类致病性霉菌烟曲霉中编码P型Ca ²⁺ -ATPase的基因之间的联系。我们证明了急性内质网应激会增加srcA的转录基因，编码肌浆/内质网Ca的成员²⁺ -ATPase（SERCA）家族，以及那的PMRA，编码分泌途径的Ca ²⁺在高尔基体膜-ATPase（SPCA）。UPR转录因子HacA的丢失阻止了ER应激期间srcA和pmrA转录的诱导，从而将这些ER / Golgi Ca ²⁺泵定义为该途径的新型下游靶标。尽管仅删除srcA并没有造成重大缺陷，但ΔsrcA / ΔpmrA该突变体显示出严重的极性缺陷，对内质网应激高度敏感，并且毒力减弱。此外，细胞壁分析显示，在没有两个Ca ²⁺泵的情况下，甘露糖水平显着降低。该Δ HACA突变体过敏的药剂块神经钙依赖性信号，与UPR和Ca之间的功能性耦合一致²⁺动态平衡。在一起，这些发现表明，普遍定期审议将对增加的伴侣蛋白和折叠酶的需求与Ca ²⁺的大量涌入整合到分泌途径中，以支持真菌的生长，压力适应和致病性。