Targeting Peptidylarginine Deiminase 3 to Efficiently Suppress Herpes Simplex Virus Type 2 Infection

IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Selina Pasquero, F. Gugliesi, Matteo Biolatti, Camilla Albano, Greta Bajetto, Linda Trifirò, Stefano Raviola, Valentina Dell’Oste, M. De Andrea
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Abstract

Protein expression is regulated through multiple mechanisms, including post-translational modifications (PTMs), which can alter protein structure, stability, localization, and function. Among these, citrullination stands out due to its ability to convert arginine residues into citrulline, altering protein charge and mass. This modification is catalyzed by calcium-dependent protein arginine deiminases (PADs), enzymes implicated in various inflammatory diseases. We have recently shown that human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) exploit these enzymes to enhance their replication capabilities. Although the role of PADs in HCMV and HSV-1 infections is well documented, their involvement in HSV-2 infection has not yet been thoroughly investigated. Here, we demonstrate that HSV-2 manipulates the overall protein citrullination profile by activating three PAD isoforms: PAD2, PAD3, and PAD4. However, as previously observed during HSV-1 infection, PAD3 is the most significantly upregulated isoform, both at the mRNA and protein levels. Consistently, we demonstrate that inhibiting PAD3, either through the specific inhibitor CAY10727 or via CRISPR/Cas9-mediated gene silencing, markedly reduces HSV-2 replication and viral protein expression. Lastly, we show that CAY10727 displays an IC50 value of 0.3 μM, which is extremely close to what was previously observed for HSV-1. Overall, our findings highlight the crucial role of PAD3 in the life cycle of HSV-2 and suggest that the targeted inhibition of PAD3 may represent a promising approach for treating HSV-2 infections, especially in cases resistant to existing antiviral therapies.
靶向肽基精氨酸脱氨酶 3 有效抑制 2 型单纯疱疹病毒感染
蛋白质的表达是通过多种机制调控的,包括翻译后修饰(PTM),它可以改变蛋白质的结构、稳定性、定位和功能。其中,瓜氨酸化因能将精氨酸残基转化为瓜氨酸,从而改变蛋白质的电荷和质量而脱颖而出。这种修饰是由钙依赖性蛋白精氨酸脱氨酶(PADs)催化的,这种酶与多种炎症性疾病有关。我们最近发现,人类巨细胞病毒(HCMV)和单纯疱疹病毒 1 型(HSV-1)利用这些酶来增强它们的复制能力。虽然 PADs 在 HCMV 和 HSV-1 感染中的作用已得到充分证实,但它们在 HSV-2 感染中的参与尚未得到深入研究。在这里,我们证明了 HSV-2 通过激活三种 PAD 异构体来操纵整个蛋白质瓜氨酸化过程:PAD2、PAD3 和 PAD4。然而,正如之前在 HSV-1 感染过程中观察到的那样,PAD3 是在 mRNA 和蛋白质水平上上调最显著的同工酶。同样,我们证明,通过特异性抑制剂 CAY10727 或 CRISPR/Cas9 介导的基因沉默来抑制 PAD3,可明显减少 HSV-2 的复制和病毒蛋白的表达。最后,我们发现 CAY10727 的 IC50 值为 0.3 μM,这与之前观察到的 HSV-1 的 IC50 值极为接近。总之,我们的研究结果凸显了 PAD3 在 HSV-2 生命周期中的关键作用,并表明靶向抑制 PAD3 可能是治疗 HSV-2 感染(尤其是对现有抗病毒疗法耐药的病例)的一种很有前景的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Molecular Sciences
International Journal of Molecular Sciences Chemistry-Organic Chemistry
CiteScore
8.10
自引率
10.70%
发文量
13472
审稿时长
17.49 days
期刊介绍: The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).
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