USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex

J Exp Med. 2013 Jul 29;210(8):1575-90. doi: 10.1084/jem.20122327. Epub 2013 Jul 1.


Reversible ubiquitin modification of cell signaling molecules has emerged as a critical mechanism by which cells respond to extracellular stimuli. Although ubiquitination of TGF-β-activated kinase 1 (TAK1) is critical for NF-κB activation in T cells, the regulation of its deubiquitination is unclear. We show that USP18, which was previously reported to be important in regulating type I interferon signaling in innate immunity, regulates T cell activation and T helper 17 (Th17) cell differentiation by deubiquitinating the TAK1-TAB1 complex. USP18-deficient T cells are defective in Th17 differentiation and Usp18(-/-) mice are resistant to experimental autoimmune encephalomyelitis (EAE). In response to T cell receptor engagement, USP18-deficient T cells exhibit hyperactivation of NF-κB and NFAT and produce increased levels of IL-2 compared with the wild-type controls. Importantly, USP18 is associated with and deubiquitinates the TAK1-TAB1 complex, thereby restricting expression of IL-2. Our findings thus demonstrate a previously uncharacterized negative regulation of TAK1 activity during Th17 differentiation, suggesting that USP18 may be targeted to treat autoimmune diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Catalysis
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Gene Expression
  • Gene Knockout Techniques
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / metabolism
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • NFATC Transcription Factors / metabolism*
  • Protein Binding
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Th17 Cells / cytology*
  • Th17 Cells / immunology
  • Th17 Cells / metabolism*
  • Ubiquitin Thiolesterase
  • Ubiquitination


  • Adaptor Proteins, Signal Transducing
  • Interleukin-2
  • NF-kappa B
  • NFATC Transcription Factors
  • Receptors, Antigen, T-Cell
  • Tab1 protein, mouse
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Endopeptidases
  • Usp18 protein, mouse
  • Ubiquitin Thiolesterase