MST1 Negatively Regulates TNFα-Induced NF-κB Signaling through Modulating LUBAC Activity

Mol Cell. 2019 Mar 21;73(6):1138-1149.e6. doi: 10.1016/j.molcel.2019.01.022. Epub 2019 Feb 21.

Abstract

The nuclear factor (NF)-κB pathway plays a central role in inflammatory and immune responses, with aberrant activation of NF-κB signaling being implicated in various human disorders. Here, we show that mammalian ste20-like kinase 1 (MST1) is a previously unrecognized component of the tumor necrosis factor α (TNFα) receptor 1 signaling complex (TNF-RSC) and attenuates TNFα-induced NF-κB signaling. Genetic ablation of MST1 in mouse embryonic fibroblasts and bone marrow-derived macrophages potentiated the TNFα-induced increase in IκB kinase (IKK) activity, as well as the expression of NF-κB target genes. TNFα induced the recruitment of MST1 to TNF-RSC and its interaction with HOIP, the catalytic component of the E3 ligase linear ubiquitin assembly complex (LUBAC). Furthermore, MST1 activated in response to TNFα stimulation mediates the phosphorylation of HOIP and thereby inhibited LUBAC-dependent linear ubiquitination of NEMO/IKKγ. Together, our findings suggest that MST1 negatively regulates TNFα-induced NF-κB signaling by targeting LUBAC.

Keywords: HOIP; LUBAC; MST1; NF-κB; TNFα; TNFα receptor 1 signaling complex; TRAF2; inflammation; macrophage; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fibroblasts / drug effects*
  • Fibroblasts / enzymology
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Macrophages / drug effects*
  • Macrophages / enzymology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multienzyme Complexes
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Intracellular Signaling Peptides and Proteins
  • Multienzyme Complexes
  • NEMO protein, mouse
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor, Type I
  • TNF Receptor-Associated Factor 2
  • TRAF2 protein, mouse
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • RNF31 protein, human
  • Rnf31 protein, mouse
  • Ubiquitin-Protein Ligases
  • STK4 protein, human
  • Stk4 protein, mouse
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • Ikbke protein, mouse