| Authors |
Ramachandran B, Stabley JN, Cheng SL, Behrmann AS, Gay A, Li L, Mead M,
Kozlitina J, Lemoff A, Mirzaei H, Chen Z, Towler DA
|
| Submitted By |
Dwight Towler on 5/2/2018 |
| Status |
Published |
| Journal |
The Journal of biological chemistry |
| Year |
2018 |
| Date Published |
4/1/2018 |
| Volume : Pages |
Not Specified : Not Specified |
| PubMed Reference |
29626090 |
| 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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