| First Author | Tang Y | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 20 | Pages | 7578-7591 |
| PubMed ID | 29650758 | Mgi Jnum | J:263682 |
| Mgi Id | MGI:6189659 | Doi | 10.1074/jbc.RA118.002727 |
| Citation | Tang Y, et al. (2018) The fructose-2,6-bisphosphatase TIGAR suppresses NF-kappaB signaling by directly inhibiting the linear ubiquitin assembly complex LUBAC. J Biol Chem 293(20):7578-7591 |
| abstractText | 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-kappaB activation. We found that TIGAR potently inhibits NF-kappaB-dependent gene expression by suppressing the upstream activation of IKKbeta 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 IKKbeta and other downstream targets. Furthermore, a TIGAR phosphatase activity-deficient mutant was equally effective as WT TIGAR in inhibiting NEMO linear ubiquitination, IKKbeta phosphorylation/activation, and NF-kappaB signaling, indicating that TIGAR's effect on NF-kappaB signaling is due to its interaction with LUBAC. Physiologically, TIGAR knockout mice displayed enhanced adipose tissue NF-kappaB signaling, whereas adipocyte-specific overexpression of TIGAR suppressed adipose tissue NF-kappaB signaling. Together, these results demonstrate that TIGAR has a nonenzymatic molecular function that modulates the NF-kappaB signaling pathway by directly inhibiting the E3 ligase activity of LUBAC. |
