Usp18 inhibits NF-κb and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex

Xikui Liu, Hongxiu Li, Bo Zhong, Marzenna Blonska, Sara Gorjestani, Ming Yan, Qiang Tian, Dong Er Zhang, Xin Lin, Chen Dong

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Reversible ubiquitin modification of cell signaling molecules has emerged as a critical mechanism by which cells respond to extracellular stimuli. Although ubiquitination of TGF-?- activated kinase 1 (TAK1) is critical for NF-?B 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-?B 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.

Original languageEnglish (US)
Pages (from-to)1575-1590
Number of pages16
JournalJournal of Experimental Medicine
Volume210
Issue number8
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Liu, X., Li, H., Zhong, B., Blonska, M., Gorjestani, S., Yan, M., Tian, Q., Zhang, D. E., Lin, X., & Dong, C. (2013). Usp18 inhibits NF-κb and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. Journal of Experimental Medicine, 210(8), 1575-1590. https://doi.org/10.1084/jem.20122327