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A GTPase-activating protein binding protein (G3BP1) / antiviral protein relay conveys arteriosclerotic Wnt signals in aortic smooth muscle cells.

A GTPase-activating protein binding protein (G3BP1) / antiviral protein relay conveys arteriosclerotic Wnt signals in aortic smooth muscle cells.
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Ramachandran B, Stabley JN, Cheng SL, Behrmann AS, Gay A, Li L, Mead M, Kozlitina J, Lemoff A, Mirzaei H, Chen Z, Towler DA,


Ramachandran B, Stabley JN, Cheng SL, Behrmann AS, Gay A, Li L, Mead M, Kozlitina J, Lemoff A, Mirzaei H, Chen Z, Towler DA, (click to view)

Ramachandran B, Stabley JN, Cheng SL, Behrmann AS, Gay A, Li L, Mead M, Kozlitina J, Lemoff A, Mirzaei H, Chen Z, Towler DA,

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The Journal of biological chemistry 2018 04 06() pii jbc.RA118.002046
Abstract

In aortic vascular smooth muscle (VSM), the canonical Wnt receptor LRP6 inhibits protein arginine (Arg) methylation, a new component of noncanonical Wnt signaling that stimulates nuclear factor of activated T cells (viz., NFATc4). To better understand how methylation mediates these actions, mass spectrometry was performed on VSM cell extracts from control and LRP6-deficient mice. LRP6-dependent Arg methylation was regulated on > 500 proteins; only 21 exhibited increased monomethylation (MMA) with concomitant reductions in dimethylation. G3BP1 – a known regulator of arteriosclerosis — exhibited a >30-fold increase in MMA in its C-terminal domain. Co-transfection studies confirm that G3BP1 methylation is inhibited by LRP6, and that G3BP1 stimulates NFATc4 transcription. NFATc4 association with VSM osteopontin (OPN) and alkaline phosphatase (TNAP) chromatin was increased with LRP6 deficiency and reduced with G3BP1 deficiency. G3BP1 activation of NFATc4 mapped to G3BP1 domains supporting interactions with RIG-I — a stimulus for mitochondrial antiviral signaling (MAVS) that ¬†drives cardiovascular calcification in humans when mutated in Singleton-Merten ¬†Syndrome (SGMRT2). Gain-of-function SGMRT2/RIG-I mutants increased G3BP1 methylation, and synergized with osteogenic transcription factors (Runx2, NFATc4). A chemical antagonist of G3BP, C108, down-regulated RIG-I -stimulated G3BP1 methylation, Wnt/NFAT signaling, VSM TNAP activity and calcification. G3BP1 deficiency reduced RIG-I protein levels and VSM osteogenic programs. Like G3BP1 and RIG-I deficiency, MAVS deficiency reduced VSM osteogenic signals – including TNAP activity and Wnt5-dependent nuclear NFATc4 levels. Aortic calcium accumulation is decreased in MAVS-deficient LDLR-/- mice fed arteriosclerotic diets. The G3BP1/RIG-I/MAVS relay is a component of Wnt signaling. Targeting this relay may help mitigate arteriosclerosis.

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