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

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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
Externally publishedYes

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T-Lymphocytes
Interleukin-2
Th17 Cells
Interferon Type I
Autoimmune Experimental Encephalomyelitis
Ubiquitination
Ubiquitin
T-Cell Antigen Receptor
Innate Immunity
Autoimmune Diseases
Cell Differentiation
Phosphotransferases

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Usp18 inhibits NF-κb and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. / Liu, Xikui; Li, Hongxiu; Zhong, Bo; Blonska, Marzenna; Gorjestani, Sara; Yan, Ming; Tian, Qiang; Zhang, Dong Er; Lin, Xin; Dong, Chen.

In: Journal of Experimental Medicine, Vol. 210, No. 8, 2013, p. 1575-1590.

Research output: Contribution to journalArticle

Liu, X, Li, H, Zhong, B, Blonska, M, Gorjestani, S, Yan, M, Tian, Q, Zhang, DE, 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, vol. 210, no. 8, pp. 1575-1590. https://doi.org/10.1084/jem.20122327
Liu, Xikui ; Li, Hongxiu ; Zhong, Bo ; Blonska, Marzenna ; Gorjestani, Sara ; Yan, Ming ; Tian, Qiang ; Zhang, Dong Er ; Lin, Xin ; Dong, Chen. / Usp18 inhibits NF-κb and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. In: Journal of Experimental Medicine. 2013 ; Vol. 210, No. 8. pp. 1575-1590.
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AU - Blonska, Marzenna

AU - Gorjestani, Sara

AU - Yan, Ming

AU - Tian, Qiang

AU - Zhang, Dong Er

AU - Lin, Xin

AU - Dong, Chen

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AB - 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.

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