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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.

Author information

1
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
2
Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
3
Institute for Immunology, Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, China.

Abstract

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.

PMID:
26829767
PMCID:
PMC4919114
DOI:
10.1038/ni.3352
[Indexed for MEDLINE]
Free PMC Article

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