一氧化氮可减弱内质网膜上PI4P的积累，从而选择性地抑制脑心肌炎病毒（EMCV）在β细胞中的复制。

IF 4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biological Chemistry Pub Date : 2025-10-07 DOI:10.1016/j.jbc.2025.110798

Alyssa L Gehant,Joshua D Stafford,Polly A Hansen,Katherine R Harty,Aaron Naatz,John A Corbett

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引用次数: 0

摘要

病毒感染，特别是小核糖核酸病毒家族成员的感染，与自身免疫性糖尿病（T1D）发病有关。脑心肌炎病毒（EMCV）是小核糖核酸病毒家族的一种嗜鼠型成员，可刺激先天免疫激活，导致细胞因子的产生。在细胞因子的作用下，β-细胞表达诱导型一氧化氮合酶（iNOS）并产生低微摩尔水平的自由基，一氧化氮。我们之前已经证明，由于其对线粒体氧化和细胞ATP消耗的抑制作用，一氧化氮选择性地减弱了EMCV在β-细胞中的复制和裂解。在这项研究中，我们发现一氧化氮抑制EMCV复制的一种机制是通过减少内质网（ER）膜上磷脂酰肌醇-4-磷酸（PI4P）的积累。因此，阻止了病毒复制复合体的形成，有效地防止了病毒复制。与先前的研究一致，我们表明这些观察结果对β细胞是选择性的，并且由于细胞ATP的损失。

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Nitric oxide attenuates PI4P accumulation at the ER membrane to inhibit encephalomyocarditis virus (EMCV) replication selectively in β-cells.

Viral infection, particularly by members of the picornavirus family, has been associated with autoimmune diabetes (T1D) onset. The encephalomyocarditis virus (EMCV) is a mouse-tropic member of the picornavirus family that stimulates innate immune activation, leading to the production of cytokines. In response to cytokines, β-cells express inducible nitric oxide synthase (iNOS) and produce low micromolar levels of the free radical, nitric oxide. We have previously shown that, due to its inhibitory action on mitochondrial oxidation and depletion of cellular ATP, nitric oxide selectively attenuates EMCV replication in and lysis of β-cells. In this study, we show that one mechanism by which nitric oxide inhibits EMCV replication is by attenuating the accumulation of phosphatidylinositol-4-phosphate (PI4P) at the endoplasmic reticulum (ER) membrane. As a result, viral replication complex formation is prohibited, and viral replication is effectively prevented. In agreement with previous studies, we show that these observations are selective for β-cells and due to a loss of cellular ATP.

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来源期刊

Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry

自引率

4.20%

发文量

1233

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