Modeling the post-translational modifications and its effects in the NF-κB pathway

Abstract

The transcriptional activities of NFKB1 and NFKB2 complexes are regulated by several post-translational modifications at different sites of these complexes. The post-translational modifications reported in the literature include phosphorylation, methylation, acetylation, sulphydration, nitrosylation, ubiquitination and sumoylation. We present a pathway network model with 172 proteins, 313 molecular species and 476 reactions including degradation of IkB (NFKBIA), proteolytic processing, and posttranslational modifications on p65 (RELA), RELB, p50 (NFKB1), and p52 (NFKB2) proteins. Comparing with experimental data on the over expression or knockouts of specific genes afforded qualitative agreement between model predictions and the experimental results. NFKB1:RELA complex is activated by active IKBKB, PIN1, MAP3K14 but repressed by PPARG and PDLIM2. MAP3K14 and UBE2I enhance the NFKB2:RELB activity, whereas NLRP12 is its repressor. The constitutive activation of NFKB1 complex through positive regulation of group of cytokines (IL1, IL1B and IL6) and IKK complex (alpha, beta and gamma) could be annulled by activation of PPARG, PIAS3 and P50-homodimer together instead of individual activations. Thus, the presented network pathway model has predictive utility in inferring NF-{kappa}B activity.