Figure 15.

Arteriosclerotic G3BP1/RIG-I signaling in aortic VSM, a working model. We (9) and others (14) previously identified that LRP6 expression in VSM restrains noncanonical Wnt signals that (a) promote phenotype modulation and neointima formation and (b) enhance arteriosclerotic mineralization. We demonstrated that protein Arg methylation is profoundly altered with LRP6 deficiency and have identified G3BP1 as a key MMA target that is negatively regulated by LRP6. We further show that RIG-I, also known as Ddx58, functionally and physically interacts with G3BP1 to enhance G3BP1 Arg methylation and the noncanonical Wnt/NFAT pathway. This is mediated in part via NFATc4 nuclear translocation and association with osteogenic genomic targets such as the OPN and TNAP promoters. The mechanisms whereby nuclear Runx2 transactivation is enhanced by the G3BP1/cRIG-I cascade have yet to be determined (indicated by the ?). Not shown are the contributions of nuclear USF1 and Sp1 recently identified as also held in check by VSM LRP6 signaling (9, 14). See text for details.