Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue.
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.
Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Edoardo
E
Fiorillo
Valeria
V
Orrú
Stephanie M
SM
Stanford
Yingge
Y
Liu
Mogjiborahman
M
Salek
Novella
N
Rapini
Aaron D
AD
Schenone
Patrizia
P
Saccucci
Lucia G
LG
Delogu
Federica
F
Angelini
Maria Luisa
ML
Manca Bitti
Christian
C
Schmedt
Andrew C
AC
Chan
Oreste
O
Acuto
Nunzio
N
Bottini
D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D010766:Phosphorylation / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases
D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; C000631346:CSK protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22