The fructose-2,6-bisphosphatase TIGAR suppresses NF-B signaling by directly inhibiting the linear ubiquitin assembly complex LUBAC

Yan Tang, Hyokjoon Kwon, Brian A. Neel, Michal Kasher-Meron, Jacob B. Pessin, Eijiro Yamada, Jeffrey E. Pessin

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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-in-duced glycolysis and apoptosis regulator) critically regulates NF-B activation. We found that TIGAR potently inhibits NF-B– dependent gene expression by suppressing the upstream activation of IKK 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 IKK and other downstream targets. Furthermore, a TIGAR phosphatase activity– deficient mutant was equally effective as WT TIGAR in inhibiting NEMO linear ubiquitination, IKK phosphorylation/activation, and NF-B signaling, indicating that TIGAR’s effect on NF-B signaling is due to its interaction with LUBAC. Physiologically, TIGAR knockout mice displayed enhanced adipose tissue NF-B signaling, whereas adipocyte-specific overexpression of TIGAR suppressed adipose tissue NF-B signaling. Together, these results demonstrate that TIGAR has a nonenzymatic molecular function that modulates the NF-B signaling pathway by directly inhibiting the E3 ligase activity of LUBAC.

Original languageEnglish (US)
Pages (from-to)7578-7591
Number of pages14
JournalJournal of Biological Chemistry
Volume293
Issue number20
DOIs
StatePublished - May 18 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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