Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination
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
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.
IdentifiersURN: urn:nbn:se:liu:diva-127571DOI: 10.1084/jem.20151426ISI: 000373390300008PubMedID: 26903241OAI: oai:DiVA.org:liu-127571DiVA: diva2:926157
Funding Agencies|National Institutes of Health [AI057555, AI064639, GM84459, AI104519]; Center for Inflammation and Cancer at the MD Anderson Cancer Center [P30CA016672]2016-05-042016-05-032016-05-24