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Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination
Sichuan University, Peoples R China; University of Texas MD Anderson Cancer Centre, TX 77030 USA.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. University of Texas MD Anderson Cancer Centre, TX 77030 USA.
University of Texas MD Anderson Cancer Centre, TX 77030 USA; Shanghai Jiao Tong University, Peoples R China.
University of Texas MD Anderson Cancer Centre, TX 77030 USA; Zhejiang University, Peoples R China.
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2016 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 213, no 3, 399-414 p.Article in journal (Refereed) PublishedText
Abstract [en]

Signal transduction from the T cell receptor (TCR) is crucial for T cell-mediated immune responses and, when deregulated, also contributes to the development of autoimmunity. How TCR signaling is regulated is incompletely understood. In this study, we demonstrate a ubiquitin-dependent mechanism in which the deubiquitinase Otud7b has a crucial role in facilitating TCR signaling. Upon TCR ligation, Otud7b is rapidly recruited to the tyrosine kinase Zap70, a central mediator of TCR-proximal signaling. Otud7b deficiency attenuates the activation of Zap70 and its downstream pathways and impairs T cell activation and differentiation, rendering mice refractory to T cell-mediated autoimmune and inflammatory responses. Otud7b facilitated Zap70 activation by deubiquitinating Zap70, thus preventing the association of Zap70 with the negative-regulatory phosphatases Sts1 and Sts2. These findings establish Otud7b as a positive regulator of TCR-proximal signaling and T cell activation, highlighting the importance of deubiquitination in regulating Zap70 function.

Place, publisher, year, edition, pages
ROCKEFELLER UNIV PRESS , 2016. Vol. 213, no 3, 399-414 p.
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-127571DOI: 10.1084/jem.20151426ISI: 000373390300008PubMedID: 26903241OAI: diva2:926157

Funding Agencies|National Institutes of Health [AI057555, AI064639, GM84459, AI104519]; Center for Inflammation and Cancer at the MD Anderson Cancer Center [P30CA016672]

Available from: 2016-05-04 Created: 2016-05-03 Last updated: 2016-05-24

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