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Nitric oxide attenuates PI4P accumulation at the ER membrane to inhibit encephalomyocarditis virus replication
Alyssa L Gehant1, Joshua D Stafford1, Polly A Hansen1
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Abstract:
Viral infection, particularly by members of the picornavirus family, has been associated with autoimmune diabetes (type 1 diabetes mellitus) 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 (NO) synthase and produce low micromolar levels of the free radical, NO. We have previously shown that, because of its inhibitory action on mitochondrial oxidation and depletion of cellular ATP, NO selectively attenuates EMCV replication in, and lysis of, β-cells. In this study, we show that one mechanism by which NO inhibits EMCV replication is by attenuating the accumulation of phosphatidylinositol-4-phosphate at the endoplasmic reticulum 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 because of a loss of cellular ATP.
Insights
Nitric oxide (NO) prevents encephalomyocarditis virus (EMCV) replication in beta cells by inhibiting phosphatidylinositol-4-phosphate accumulation, thus protecting against autoimmune diabetes onset.
Area of Science:
- Immunology
- Virology
- Endocrinology
Background:
- Picornavirus infections are linked to autoimmune diabetes (type 1 diabetes mellitus).
- Encephalomyocarditis virus (EMCV) triggers innate immunity and cytokine production.
- Beta cells produce nitric oxide (NO) in response to cytokines, which inhibits EMCV replication and beta cell lysis.
Purpose of the Study:
- To elucidate the mechanism by which NO inhibits EMCV replication in beta cells.
- To investigate the role of NO in protecting beta cells from viral-induced damage.
Main Methods:
- Investigated the effect of NO on phosphatidylinositol-4-phosphate accumulation at the endoplasmic reticulum membrane.
- Assessed the impact of NO on viral replication complex formation.
- Examined the selectivity of NO's inhibitory effects on EMCV in beta cells.
Main Results:
- NO attenuates the accumulation of phosphatidylinositol-4-phosphate at the endoplasmic reticulum membrane.
- This inhibition prevents viral replication complex formation and viral replication.
- These effects are selective for beta cells and linked to ATP depletion.
Conclusions:
- NO inhibits EMCV replication by disrupting phosphatidylinositol-4-phosphate metabolism at the ER membrane.
- This mechanism protects beta cells from viral infection and lysis.
- NO's protective role in beta cells may have implications for preventing type 1 diabetes.
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