USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1–TAB1 complex
Year: 2013
Type: article
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-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.
DOI: 10.1084/jem.20122327
Authors: Xikui Liu, Hongxiu Li, Bo Zhong, Marzenna Blonska, Sara Gorjestani, Ming Yan, Qiang Tian, Dong-Er Zhang, Xin Lin, Chen Dong
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Awards: Signal Transduction and Cytokine Gene Regulation by Grail, Signal Transduction and Cytokine Gene Regulation by Grail, G4049846610, CARMA1-mediated NF-kB activation in lymphocyte activation, G4575832443, G4727569337, T Cell receptor-induced NF-kB and JNK activation, G5505166270, Transcriptional regulation of inflammatory helper T Cell differentiation, Mechanism of host innate immune system sensing Candida albicans infection, The function of CARD9 in innate immune responses, Cancer Center Support Grant
OpenAlex ID: W2107797460