The systems integration of whole-body metabolism and immune signaling are central homeostatic mechanisms necessary for maintenance of normal physiology, and dysregulation of these processes leads to a variety of chronic disorders. However, the intracellular mechanisms responsible for cell-autonomous cross-talk between the inflammatory signaling pathways and metabolic flux have remained enigmatic. In this study, we discovered that the fructose-2,6-bisphosphatase TIGAR (Tp53-induced glycolysis and apoptosis regulator) critically regulates NF-κB activation. We found that TIGAR potently inhibits NF-κB-dependent gene expression by suppressing the upstream activation of IKKβ phosphorylation and kinase activation. This inhibition occurred through a direct binding competition between NEMO and TIGAR for association with the linear ubiquitination assembly complex (LUBAC). This competition prevented linear ubiquitination of NEMO, which is required for activation of IKKβ and other downstream targets. Furthermore, a TIGAR phosphatase activity-deficient mutant was equally effective as WT TIGAR in inhibiting NEMO linear ubiquitination, IKKβ phosphorylation/activation, and NF-κB signaling, indicating that TIGAR's effect on NF-κB signaling is due to its interaction with LUBAC. Physiologically, TIGAR knockout mice displayed enhanced adipose tissue NF-κB signaling, whereas adipocyte-specific overexpression of TIGAR suppressed adipose tissue NF-κB signaling. Together, these results demonstrate that TIGAR has a nonenzymatic molecular function that modulates the NF-κB signaling pathway by directly inhibiting the E3 ligase activity of LUBAC.
Keywords: IKKbeta; LUBAC; NF-kappaB (NF-KB); NF-κB; TIGAR; adipocyte; adipocytes; linear ubiquitination; p53; ubiquitin ligase; ubiquitylation (ubiquitination).
© 2018 Tang et al.