Autoimmune-associated PTPN22 R620W Variation Reduces Phosphorylation of Lymphoid Phosphatase on an Inhibitory Tyrosine Residue

被引:80
作者
Fiorillo, Edoardo [2 ]
Orru, Valeria [2 ]
Stanford, Stephanie M. [1 ,2 ]
Liu, Yingge [2 ]
Salek, Mogjiborahman [3 ]
Rapini, Novella [4 ]
Schenone, Aaron D. [1 ]
Saccucci, Patrizia [5 ]
Delogu, Lucia G. [2 ]
Angelini, Federica [4 ]
Bitti, Maria Luisa Manca [4 ]
Schmedt, Christian [6 ]
Chan, Andrew C. [7 ]
Acuto, Oreste [3 ]
Bottini, Nunzio [1 ,2 ]
机构
[1] La Jolla Inst Allergy & Immunol, Div Cell Biol, La Jolla, CA 92037 USA
[2] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90033 USA
[3] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England
[4] Tor Vergata Univ, Dept Pediat, I-00133 Rome, Italy
[5] Tor Vergata Univ, Dept Biopathol, I-00133 Rome, Italy
[6] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA
[7] Genentech Inc, Div Immunol, San Francisco, CA 94080 USA
基金
美国国家卫生研究院;
关键词
CELL ANTIGEN RECEPTOR; TERMINAL SRC KINASE; T-CELLS; PROTEIN; PHOSPHOTYROSINE; ACTIVATION; PEPTIDE; VARIANT; DOMAIN; PEP;
D O I
10.1074/jbc.M110.111104
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. PTPN22 encodes the lymphoid tyrosine phosphatase (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling through the T cell receptor. The C1858T single nucleotide polymorphism results in the LYP-R620W variation within the LYP-Csk interaction motif. LYP-W620 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively interacts with its substrate Lck in a Csk-dependent manner. T cell receptor-induced phosphorylation of LYP by Lck on an inhibitory tyrosine residue releases tonic inhibition of signaling by LYP. The R620W variation disrupts the interaction between Lck and LYP, leading to reduced phosphorylation of LYP, which ultimately contributes to gain-of-function inhibition of T cell signaling.
引用
收藏
页码:26506 / 26518
页数:13
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