title: SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex.
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.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Park
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Hyung-Seung
authors.initials: HS
authors.lastname: Jin
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Lopez
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Jeeho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Elly
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|Institute for Immunology, Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D015151:Immunoblotting; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D054875:Ubiquitination; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; C554944:Sipl1 protein, mouse; C054979:antigen T cell receptor, zeta chain; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse
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