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. 2018 Apr 6;293(21):7942–7968. doi: 10.1074/jbc.RA118.002046

Figure 10.

Figure 10.

Constitutively active, pro-arteriosclerotic variants of Ddx58/RIG-I enhance G3BP1-stimulated transcription. The RIG-I/Ddx58 variants Ddx58(E373A) and Ddx58(C268F) have recently been identified to cause Singleton-Merten syndrome and characterized by precocious aortic, aortic valve, and coronary calcification (39). A, G3BP1 + RIG-I(E373A) activation of NFAT transcription (NFATc4) requires intact G3BP1 NTF2 and C-terminal Arg methylation domains. RIG-I(E373A) is hence denoted as cRIG-I. **, p ≤ 0.01 versus control lacking any expression vector (far left, control); NS, not significant. B, cRIG-I activation of NFATc4 is inhibited by LRP6 expression. ***, p ≤ 0.001 versus control. #, p ≤ 0.001 versus cRIG-I. C, as compared with WT G3BP1, G3BP1(R460Q) is not capable of synergizing with cRIG-I to activate NFAT signaling (NFATc4 co-expression). ***, p ≤ 0.001 versus all others. D, both RIG-I/Ddx58 variants RIG-I (E373A) and RIG-I (C268F) exhibit gain-of-function synergy with Runx2 activation of the OPN promoter. ***, p ≤ 0.001 versus RIG-I and all others. ****, p < 0.0001 versus G3BP1 + Runx2 + RIG-I. E, Runx2 but not Runx1 is active in this assay. ***, p ≤ 0.001 versus Runx2 + G3BP1, and #, p ≤ 0.01 versus pCMV control. F, cRIG-I activation of the OPN promoter requires the G3BP1 C-terminal Arg methylation domain. #, p ≤ 0.001 versus all others, and ***, p ≤ 0.001 versus G3BP1 + Runx2 with cRIG-I.