Protein methyltransferase 7 deficiency in Leishmania major increases neutrophil associated pathology in murine model.
Protein methyltransferase 7 deficiency in Leishmania major increases neutrophil associated pathology in murine model.
复制标题
在小鼠模型中，硕大利什曼原虫蛋白甲基转移酶7缺乏增加了中性粒细胞相关病理。
DOI：
10.1371/journal.pntd.0009230
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发表时间：
2021-03
影响因子：
3.8
通讯作者：
Cruz AK
中科院分区：
文献类型：
--
作者：
Alcoforado Diniz J;Chaves MM;Vaselek S;Miserani Magalhães RD;Ricci-Azevedo R;de Carvalho RVH;Lorenzon LB;Ferreira TR;Zamboni D;Walrad PB;Volf P;Sacks DL;Cruz AK
硕大利什曼原虫是旧大陆皮肤利什曼病的主要病原体。在利什曼原虫中，转录控制的缺乏主要由转录后机制补偿。精氨酸的甲基化是由蛋白质精氨酸甲基转移酶（PRMT）执行的保守的翻译后修饰。L.主要编码五个PRMT同源物，包括与几种RNA结合蛋白相关的胞质蛋白，LmjPRMT 7。先前已报道LmjPRMT7可影响寄生虫感染性。此外，最近的一项工作清楚地表明了LmjPRMT 7在甲基化靶点的RNA结合能力和蛋白质稳定性方面的重要性，证明了这种酶作为mRNA代谢的重要表观遗传调节因子的作用。在这项研究中，我们揭示了PRMT7介导的甲基化对寄生虫发育和毒力的影响。我们的数据显示，较高水平的LmjPRMT7可以削弱寄生虫的致病性，并且该酶的缺失挽救了减毒株的致病性表型。少校有趣的是，由LmjPRMT7敲除寄生虫引起的病变形成与组织中与过度嗜中性粒细胞募集相关的炎症反应加剧有关。此外，LmjPRMT7的缺乏也损害了白蛉媒介杜氏白蛉（Phlebotomus duboscqi）内的寄生虫发育。最后，转录组分析揭示了受这种酶耗尽影响的可能基因。总之，这项研究强调了转录后调控如何影响寄生虫生物学的不同方面。了解利什曼原虫（一种引起利什曼病的原生动物寄生虫）的遗传学，对于了解病原体生物学及其与宿主相互作用的基本问题是相关的。我们探索利什曼原虫迅速适应不同宿主的机制，研究寄生虫中转录后水平发生的基因表达控制。通过蛋白质精氨酸甲基转移酶（PRMT）进行的精氨酸甲基化，以及其他翻译后修饰，可以改变靶蛋白的功能和相互作用，其中一些是RNA结合蛋白，已知的基因表达调节剂。在这项研究中，我们揭示了PRMT7对寄生虫发育和致病性的影响。除了LmjPRMT 7水平与寄生虫致病性之间的负相关性之外，我们还观察到白蛉媒介中寄生虫发育的损害。值得注意的是，尽管在小鼠中发生了严重的病变，但我们观察到用致病性LmjPRMT7敲除寄生虫或减毒亲本系感染之间的寄生虫负荷没有差异。相反，观察到的重度病理学与炎症反应加剧相关，炎症反应加剧与中性粒细胞过度募集相关。
Leishmania major is the main causative agent of cutaneous leishmaniasis in the Old World. In Leishmania parasites, the lack of transcriptional control is mostly compensated by post-transcriptional mechanisms. Methylation of arginine is a conserved post-translational modification executed by Protein Arginine Methyltransferase (PRMTs). The genome from L. major encodes five PRMT homologs, including the cytosolic protein associated with several RNA-binding proteins, LmjPRMT7. It has been previously reported that LmjPRMT7 could impact parasite infectivity. In addition, a more recent work has clearly shown the importance of LmjPRMT7 in RNA-binding capacity and protein stability of methylation targets, demonstrating the role of this enzyme as an important epigenetic regulator of mRNA metabolism. In this study, we unveil the impact of PRMT7-mediated methylation on parasite development and virulence. Our data reveals that higher levels of LmjPRMT7 can impair parasite pathogenicity, and that deletion of this enzyme rescues the pathogenic phenotype of an attenuated strain of L. major. Interestingly, lesion formation caused by LmjPRMT7 knockout parasites is associated with an exacerbated inflammatory reaction in the tissue correlated with an excessive neutrophil recruitment. Moreover, the absence of LmjPRMT7 also impairs parasite development within the sand fly vector Phlebotomus duboscqi. Finally, a transcriptome analysis shed light onto possible genes affected by depletion of this enzyme. Taken together, this study highlights how post-transcriptional regulation can affect different aspects of the parasite biology. Understanding the genetics of Leishmania, a protozoan parasite causing leishmaniasis, is relevant for understanding fundamental questions on the pathogen’s biology and its interaction with hosts. We explore mechanisms used by Leishmania to promptly adapt to different hosts investigating the control of gene expression occurring at the post-transcriptional level in the parasite. Methylation of arginine performed by Protein Arginine Methyltransferase (PRMTs), among other post-translational modifications, may alter the function and interactions of target proteins, some of them are RNA binding proteins, known regulators of gene expression. In this study, we unveil the impact of PRMT7 on parasite development and pathogenicity. In addition to a negative correlation between the levels of LmjPRMT7 and parasite pathogenicity, we observed an impairment of the parasite development in the sand fly vector. Remarkably, despite a severe lesion development in mice, we observed no differences in parasite burden between infections with the pathogenic LmjPRMT7 knockout parasite or the attenuated parental line. Instead, the severe pathology observed is associated with an exacerbated inflammatory response correlated with excessive neutrophil recruitment.
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影响因子：
48
作者：
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通讯作者：
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影响因子：
6.7
作者：
Chaves, Mariana M.;Sinflorio, Debora A.;Coutinho-Silva, Robson
通讯作者：
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影响因子：
82.9
作者：
Lima-Junior, Djalma S.;Costa, Diego L.;Zamboni, Dario S.
通讯作者：
Zamboni, Dario S.
影响因子：
12.3
作者：
Law CW;Chen Y;Shi W;Smyth GK
通讯作者：
Smyth GK
QualiMap 2：高通量测序数据的高级多样本质量控制。
DOI：
10.1093/bioinformatics/btv566
发表时间：
2016-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Okonechnikov K;Conesa A;García-Alcalde F
通讯作者：
García-Alcalde F