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Scanning Quadrupole Data-Independent Acquisition, Part B: Application to the Analysis of the Calcineurin-Interacting Proteins during Treatment of Aspergillus fumigatus with Azole and Echinocandin Antifungal Drugs
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2017-12-29 00:00:00 , DOI: 10.1021/acs.jproteome.7b00499 Praveen R. Juvvadi 1 , M. Arthur Moseley 2 , Christopher J. Hughes 3 , Erik J. Soderblom 2 , Sarah Lennon 3 , Simon R. Perkins 4 , J. Will Thompson 2 , Scott J. Geromanos 5 , Jason Wildgoose 3 , Keith Richardson 3 , James I. Langridge 3 , Johannes P. C. Vissers 3 , William J. Steinbach 1, 6
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2017-12-29 00:00:00 , DOI: 10.1021/acs.jproteome.7b00499 Praveen R. Juvvadi 1 , M. Arthur Moseley 2 , Christopher J. Hughes 3 , Erik J. Soderblom 2 , Sarah Lennon 3 , Simon R. Perkins 4 , J. Will Thompson 2 , Scott J. Geromanos 5 , Jason Wildgoose 3 , Keith Richardson 3 , James I. Langridge 3 , Johannes P. C. Vissers 3 , William J. Steinbach 1, 6
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Calcineurin is a critical cell-signaling protein that orchestrates growth, stress response, virulence, and antifungal drug resistance in several fungal pathogens. Blocking calcineurin signaling increases the efficacy of several currently available antifungals and suppresses drug resistance. We demonstrate the application of a novel scanning quadrupole DIA method for the analysis of changes in the proteins coimmunoprecipitated with calcineurin during therapeutic antifungal drug treatments of the deadly human fungal pathogen Aspergillus fumigatus. Our experimental design afforded an assessment of the precision of the method as demonstrated by peptide- and protein-centric analysis from eight replicates of the study pool QC samples. Two distinct classes of clinically relevant antifungal drugs that are guideline recommended for the treatment of invasive “aspergillosis” caused by Aspergillus fumigatus, the azoles (voriconazole) and the echinocandins (caspofungin and micafungin), which specifically target the fungal plasma membrane and the fungal cell wall, respectively, were chosen to distinguish variations occurring in the proteins coimmunoprecipitated with calcineurin. Novel potential interactors were identified in response to the different drug treatments that are indicative of the possible role for calcineurin in regulating these effectors. Notably, treatment with voriconazole showed increased immunoprecipitation of key proteins involved in membrane ergosterol biosynthesis with calcineurin. In contrast, echinocandin (caspofungin or micafungin) treatments caused increased immunoprecipitation of proteins involved in cell-wall biosynthesis and septation. Furthermore, abundant coimmunoprecipitation of ribosomal proteins with calcineurin occurred exclusively in echinocandins treatment, indicating reprogramming of cellular growth mechanisms during different antifungal drug treatments. While variations in the observed calcineurin immunoprecipitated proteins may also be due to changes in their expression levels under different drug treatments, this study suggests an important role for calcineurin-dependent cellular mechanisms in response to antifungal treatment of A. fumigatus that warrants future studies.
中文翻译：
扫描四极杆独立于数据的采集，B部分：在用唑和棘孢菌素抗真菌药物治疗烟曲霉过程中钙调磷酸酶相互作用蛋白的分析中的应用
钙调神经磷酸酶是一种重要的细胞信号蛋白，可在几种真菌病原体中协调生长，应激反应，毒力和抗真菌药物耐药性。阻断钙调神经磷酸酶信号传导可提高几种目前可用的抗真菌药的功效，并抑制药物耐药性。我们展示了一种新型的扫描四极杆DIA方法的应用，用于分析致命的人类真菌病原体烟曲霉的抗真菌药物治疗过程中与钙调神经磷酸酶共免疫沉淀的蛋白质的变化。我们的实验设计提供了对方法精度的评估，如通过对研究池QC样品的八次重复进行的以肽和蛋白质为中心的分析所证实的。推荐用于治疗由烟曲霉引起的浸润性“曲霉病”的两种不同类别的临床相关抗真菌药物分别选择了分别针对真菌质膜和真菌细胞壁的唑类（伏立康唑）和棘球ins素（卡泊芬净和米卡芬净），以区分在与钙调神经磷酸酶共免疫沉淀的蛋白质中发生的变异。响应不同的药物治疗，确定了新型潜在的相互作用因子，这些相互作用指示钙调神经磷酸酶在调节这些效应子中的可能作用。值得注意的是，伏立康唑治疗显示与钙调神经磷酸酶有关的膜麦角固醇生物合成中涉及的关键蛋白的免疫沉淀增加。相比之下，棘皮菌素（卡泊芬净或米卡芬净）治疗引起与细胞壁生物合成和分离有关的蛋白质的免疫沉淀增加。此外，核糖体蛋白与钙调神经磷酸酶的大量共免疫沉淀仅发生在棘球and素治疗中，这表明在不同的抗真菌药物治疗过程中细胞生长机制的重新编程。虽然观察到的钙调神经磷酸酶免疫沉淀蛋白的变化也可能是由于在不同药物治疗下其表达水平的变化所致，但这项研究表明钙调神经磷酸酶依赖性细胞机制在抗真菌治疗中起着重要的作用。A.烟权证未来的研究。
更新日期：2017-12-31
中文翻译：
扫描四极杆独立于数据的采集，B部分：在用唑和棘孢菌素抗真菌药物治疗烟曲霉过程中钙调磷酸酶相互作用蛋白的分析中的应用
钙调神经磷酸酶是一种重要的细胞信号蛋白，可在几种真菌病原体中协调生长，应激反应，毒力和抗真菌药物耐药性。阻断钙调神经磷酸酶信号传导可提高几种目前可用的抗真菌药的功效，并抑制药物耐药性。我们展示了一种新型的扫描四极杆DIA方法的应用，用于分析致命的人类真菌病原体烟曲霉的抗真菌药物治疗过程中与钙调神经磷酸酶共免疫沉淀的蛋白质的变化。我们的实验设计提供了对方法精度的评估，如通过对研究池QC样品的八次重复进行的以肽和蛋白质为中心的分析所证实的。推荐用于治疗由烟曲霉引起的浸润性“曲霉病”的两种不同类别的临床相关抗真菌药物分别选择了分别针对真菌质膜和真菌细胞壁的唑类（伏立康唑）和棘球ins素（卡泊芬净和米卡芬净），以区分在与钙调神经磷酸酶共免疫沉淀的蛋白质中发生的变异。响应不同的药物治疗，确定了新型潜在的相互作用因子，这些相互作用指示钙调神经磷酸酶在调节这些效应子中的可能作用。值得注意的是，伏立康唑治疗显示与钙调神经磷酸酶有关的膜麦角固醇生物合成中涉及的关键蛋白的免疫沉淀增加。相比之下，棘皮菌素（卡泊芬净或米卡芬净）治疗引起与细胞壁生物合成和分离有关的蛋白质的免疫沉淀增加。此外，核糖体蛋白与钙调神经磷酸酶的大量共免疫沉淀仅发生在棘球and素治疗中，这表明在不同的抗真菌药物治疗过程中细胞生长机制的重新编程。虽然观察到的钙调神经磷酸酶免疫沉淀蛋白的变化也可能是由于在不同药物治疗下其表达水平的变化所致，但这项研究表明钙调神经磷酸酶依赖性细胞机制在抗真菌治疗中起着重要的作用。A.烟权证未来的研究。
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