Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 210, Issue 8, Pages 1575-1590Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20122327
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Funding
- National Institutes of Health
- MD Anderson Cancer Center [AR050772, AI50761, AI050848, GM065899]
- CFP foundation at the MD Anderson Cancer Center
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Reversible ubiquitin modification of cell signaling molecules has emerged as a critical mechanism by which cells respond to extracellular stimuli. Although ubiquitination of TGF-beta-activated kinase 1 (TAK1) is critical for NF-kappa 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-kappa 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 auto-immune diseases.
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