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.