髓鞘碱性蛋白可拮抗SARS-CoV-2蛋白ORF3a诱导的自噬抑制。

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
George A. Saratov , Alexey A. Belogurov Jr. , Anna A. Kudriaeva
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引用次数: 0

摘要

抑制自噬是 SARS-CoV-2 感染的特征之一。最近有报道称,SARS-CoV-2蛋白ORF3a通过与VPS39相互作用抑制自噬体与溶酶体的融合,从而阻止同型融合和蛋白分拣(HOPS)复合物与RAB7 GTPase的结合。在这里,我们报告了髓鞘的主要结构成分--髓鞘碱性蛋白(MBP)与 ORF3a 结合,并在哺乳动物细胞中与其共定位。在哺乳动物细胞中,MBP与ORF3a共表达可恢复被病毒蛋白抑制的自噬。我们的数据表明,由于 MBP 的脱氨基变体失去了结合 ORF3a 和抵消自噬阻断的能力,因此 MBP 的基本电荷驱动了对 ORF3a 诱导的自噬抑制的抑制。这些结果连同我们最近的研究结果表明,MBP 与囊泡转运机制的结构成分--突触体相关蛋白 23(SNAP23)、囊泡相关膜蛋白 3(VAMP3)和 Sec1/Munc18-1 家族成员--相互作用,可能表明在 SARS-CoV-2 感染期间,MBP 在维持少突胶质细胞的蛋白质转运和自噬体-溶酶体融合机制方面起着保护作用。最后,我们的数据可能表明,在多发性硬化症(MS)患者体内观察到的 MBP 消失可能是导致之前报道的 COVID-19 结果恶化和 COVID-19 后多发性硬化症患者神经症状加重的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Myelin basic protein antagonizes the SARS-CoV-2 protein ORF3a-induced autophagy inhibition

Myelin basic protein antagonizes the SARS-CoV-2 protein ORF3a-induced autophagy inhibition

Inhibition of autophagy is one of the hallmarks of the SARS-CoV-2 infection. Recently it was reported that SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes via interaction with VPS39 thus preventing binding of homotypic fusion and protein sorting (HOPS) complex to RAB7 GTPase. Here we report that myelin basic protein (MBP), a major structural component of the myelin sheath, binds ORF3a and is colocalized with it in mammalian cells. Co-expression of MBP with ORF3a restores autophagy in mammalian cells, inhibited by viral protein. Our data suggest that basic charge of MBP drives suppression of ORF3a-induced autophagy inhibition as its deaminated variants lost ability to bind ORF3a and counteract autophagy blockade. These results together with our recent findings, indicating that MBP interacts with structural components of the vesicle transport machinery-synaptosomal-associated protein 23 (SNAP23), vesicle-associated membrane protein 3 (VAMP3) and Sec1/Munc18-1 family members, may suggest protective role of the MBP in terms of the maintaining of protein traffic and autophagosome–lysosome fusion machinery in oligodendrocytes during SARS-CoV-2 infection. Finally, our data may indicate that deimination of MBP observed in the patients with multiple sclerosis (MS) may contribute to the previously reported worser outcomes of COVID-19 and increase of post-COVID-19 neurologic symptoms in patients with MS.

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来源期刊
Biochimie
Biochimie 生物-生化与分子生物学
CiteScore
7.20
自引率
2.60%
发文量
219
审稿时长
40 days
期刊介绍: Biochimie publishes original research articles, short communications, review articles, graphical reviews, mini-reviews, and hypotheses in the broad areas of biology, including biochemistry, enzymology, molecular and cell biology, metabolic regulation, genetics, immunology, microbiology, structural biology, genomics, proteomics, and molecular mechanisms of disease. Biochimie publishes exclusively in English. Articles are subject to peer review, and must satisfy the requirements of originality, high scientific integrity and general interest to a broad range of readers. Submissions that are judged to be of sound scientific and technical quality but do not fully satisfy the requirements for publication in Biochimie may benefit from a transfer service to a more suitable journal within the same subject area.
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