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Nat Immunol. 2016 Mar;17(3):286-96. doi: 10.1038/ni.3352. Epub 2016 Feb 1.

SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex.

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Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Institute for Immunology, Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, China.


SHARPIN forms a linear-ubiquitin-chain-assembly complex that promotes signaling via the transcription factor NF-κB. SHARPIN deficiency leads to progressive multi-organ inflammation and immune system malfunction, but how SHARPIN regulates T cell responses is unclear. Here we found that SHARPIN deficiency resulted in a substantial reduction in the number of and defective function of regulatory T cells (Treg cells). Transfer of SHARPIN-sufficient Treg cells into SHARPIN-deficient mice considerably alleviated their systemic inflammation. SHARPIN-deficient T cells displayed enhanced proximal signaling via the T cell antigen receptor (TCR) without an effect on the activation of NF-κB. SHARPIN conjugated with Lys63 (K63)-linked ubiquitin chains, which led to inhibition of the association of TCRζ with the signaling kinase Zap70; this affected the generation of Treg cells. Our study therefore identifies a role for SHARPIN in TCR signaling whereby it maintains immunological homeostasis and tolerance by regulating Treg cells.

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