Stovall Anna K, Knowles Corey M, Kalem Murat C, Panepinto John C
Department of Microbiology and Immunology, Witebsky Center for Microbial Pathogenesis and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA.
Front Fungal Biol. 2021 Mar;2. doi: 10.3389/ffunb.2021.640678. Epub 2021 Mar 22.
The fungal pathogen relies on post-transcriptional mechanisms of gene regulation to adapt to stressors it encounters in the human host, such as oxidative stress and nutrient limitation. The kinase Gcn2 regulates translation in response to stress by phosphorylating the initiation factor eIF2, and it is a crucial factor in withstanding oxidative stress in , and amino acid limitation in many fungal species. However, little is known about the role of Gcn2 in nitrogen limitation in . In this study, we demonstrate that Gcn2 is required for to utilize methionine as a source of nitrogen, and that the presence of methionine as a sole nitrogen source induces eIF2 phosphorylation. The stress imposed by methionine leads to an oxidative stress response at both the levels of transcription and translation, as seen through polysome profiling as well as increased abundance of select oxidative stress response transcripts. The transcription factor Gcn4 is also required for methionine utilization and oxidative stress resistance, and RT-qPCR data suggests that it regulates expression of certain transcripts in response to oxidative stress. The results of this study suggest a connection between nitrogen metabolism and oxidative stress in that is mediated by Gcn4, possibly indicating the presence of a compound stress response in this clinically important fungal pathogen.
这种真菌病原体依靠基因调控的转录后机制来适应在人类宿主中遇到的应激源，如氧化应激和营养限制。激酶Gcn2通过磷酸化起始因子eIF2来响应应激调节翻译，并且它是在许多真菌物种中抵御氧化应激和氨基酸限制的关键因素。然而，关于Gcn2在氮限制中的作用知之甚少。在本研究中，我们证明Gcn2是利用蛋氨酸作为氮源所必需的，并且蛋氨酸作为唯一氮源的存在会诱导eIF2磷酸化。蛋氨酸施加的应激在转录和翻译水平上均导致氧化应激反应，这通过多核糖体分析以及某些氧化应激反应转录本丰度的增加得以体现。转录因子Gcn4对于蛋氨酸利用和氧化应激抗性也是必需的，并且RT-qPCR数据表明它响应氧化应激调节某些转录本的表达。本研究结果表明在中氮代谢与氧化应激之间存在由Gcn4介导的联系，这可能表明在这种临床上重要的真菌病原体中存在复合应激反应。
