Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New York, United States of America.
Department of Plant Science, Gangneung-Wonju National University, Gangneung, Republic of Korea.
PLoS Genet. 2024 Oct 21;20(10):e1011455. doi: 10.1371/journal.pgen.1011455. eCollection 2024 Oct.
Human fungal pathogens must survive diverse reactive oxygen species (ROS) produced by host immune cells that can oxidize a range of cellular molecules including proteins, lipids, and DNA. Formation of lipid radicals can be especially damaging, as it leads to a chain reaction of lipid peroxidation that causes widespread damage to the plasma membrane. Most previous studies on antioxidant pathways in fungal pathogens have been conducted with hydrogen peroxide, so the pathways used to combat organic peroxides and lipid peroxidation are not well understood. The most well-known peroxidase in Candida albicans, catalase, can only act on hydrogen peroxide. We therefore characterized a family of four glutathione peroxidases (GPxs) that were predicted to play an important role in reducing organic peroxides. One of the GPxs, Gpx3 is also known to activate the Cap1 transcription factor that plays the major role in inducing antioxidant genes in response to ROS. Surprisingly, we found that the only measurable role of the GPxs is activation of Cap1 and did not find a significant role for GPxs in the direct detoxification of peroxides. Furthermore, a CAP1 deletion mutant strain was highly sensitive to organic peroxides and oxidized lipids, indicating an important role for antioxidant genes upregulated by Cap1 in protecting cells from organic peroxides. We identified GLR1 (Glutathione reductase), a gene upregulated by Cap1, as important for protecting cells from oxidized lipids, implicating glutathione utilizing enzymes in the protection against lipid peroxidation. Furthermore, an RNA-sequencing study in C. albicans showed upregulation of a diverse set of antioxidant genes and protein damage pathways in response to organic peroxides. Overall, our results identify novel mechanisms by which C. albicans responds to oxidative stress resistance which open new avenues for understanding how fungal pathogens resist ROS in the host.
人真菌病原体必须在宿主免疫细胞产生的各种活性氧（ROS）中存活，这些细胞可以氧化包括蛋白质、脂质和 DNA 在内的各种细胞分子。脂质自由基的形成尤其具有破坏性，因为它会导致脂质过氧化的连锁反应，从而对质膜造成广泛的损伤。以前关于真菌病原体抗氧化途径的大多数研究都是用过氧化氢进行的，因此，对抗有机过氧化物和脂质过氧化的途径还不是很清楚。白色念珠菌中最著名的过氧化物酶是过氧化氢酶，它只能作用于过氧化氢。因此，我们对一个被预测在减少有机过氧化物方面发挥重要作用的谷胱甘肽过氧化物酶（GPx）家族进行了特征描述。GPx 中的一种，Gpx3，也被认为可以激活 Cap1 转录因子，该因子在诱导抗氧化基因对 ROS 产生反应中起着主要作用。令人惊讶的是，我们发现 GPx 的唯一可衡量作用是激活 Cap1，并且没有发现 GPx 在直接解毒过氧化物方面有重要作用。此外，CAP1 缺失突变株对有机过氧化物和氧化脂质高度敏感，这表明 Cap1 上调的抗氧化基因在保护细胞免受有机过氧化物的侵害方面起着重要作用。我们确定了 GLR1（谷胱甘肽还原酶），这是一种被 Cap1 上调的基因，对保护细胞免受氧化脂质的伤害非常重要，这表明谷胱甘肽利用酶在防止脂质过氧化中起作用。此外，白色念珠菌的 RNA 测序研究显示，在响应有机过氧化物时，一组多样化的抗氧化基因和蛋白质损伤途径被上调。总的来说，我们的研究结果确定了白色念珠菌应对氧化应激的新机制，为了解真菌病原体如何在宿主中抵抗 ROS 提供了新的途径。
