Nonlinear Bivariate Associations and Mononuclear Cell-Type-Specific Expression Level Differences in the STING...

Understanding intracellular signalling pathways is crucial since they regulate essential functional activities. Bivariate relationships have been useful in delineating these pathways in clinical samples. In our previous studies, we have found many linear associations between pathway components, and we have interpreted these correlations as rheostatic regulators. Increases in an upstream component are correlated with a commensurate downstream increase. Here, we report a quantitative analysis of molecules in the STING pathway by assessing the variance in human peripheral blood mononuclear cell-type-specific molecular expression from patients with atherosclerotic coronary artery disease. The induction of the type I interferon track by this pathway is dependent on the expression levels of STING in T cells and monocytes and the expression levels of phospho-STING in B cells. This relationship in T cells and monocytes demonstrates definitive linearity, indicating that it is regulated as a rheostat. In B cells the relationships are logarithmic, indicating an on-off mechanism of regulation. The STING pathway-dependent stimulation of the NFκB track is also controlled by on-off mechanisms that are modelled by nonlinear bivariate relationships. These on-off switches occur at the bifurcation of the two branches involving phospho-STING, phospho-TBK1 and phospho-RelA. Whereas linear bivariate associations are readily captured by an evaluation of the correlation matrix, significant nonlinear relationships are not. Nonlinear correlations modelled logarithmically or exponentially are easily discerned by the assessment of a natural log-transformed versus non-transformed correlation matrix.