The W620 Polymorphism in PTPN22 Disrupts Its Interaction With Peptidylarginine Deiminase Type 4 and Enhances Citrullination and NETosis

Arthritis and Rheumatology - Tập 67 Số 9 - Trang 2323-2334 - 2015
Hui‐Hsin Chang1, Nishant Dwivedi1, Anthony P. Nicholas2, I‐Cheng Ho1
1Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
2University of Alabama at Birmingham and Birmingham VA Medical Center; Birmingham Alabama

Tóm tắt

ObjectiveA C‐to‐T single‐nucleotide polymorphism (SNP) located at position 1858 of human protein tyrosine phosphatase PTPN22 complementary DNA carries the highest risk of rheumatoid arthritis (RA) among all non‐HLA genetic variants. This C1858T SNP converts an arginine (R620) to a tryptophan (W620), but it is unclear why it has such a strong impact on RA, a disease characterized by anti–citrullinated protein antibodies. The aim of this study was to test the hypothesis that PTPN22 regulates protein citrullination.MethodsThe level of citrullinated proteins in immune cells was quantified by Western blotting. The physical interaction between PTPN22 and peptidyl arginine deiminase type 4 (PAD‐4), which is one of the enzymes that catalyzes protein citrullination, was examined by coimmunoprecipitation. Neutrophils were collected from healthy donors carrying the C1858T SNP and healthy donors not carrying this SNP. The formation of neutrophil extracellular traps (NETs) was examined by immunocytochemistry.ResultsPTPN22 physically interacted with PAD‐4, and a deficiency in PTPN22 enhanced protein citrullination. This abnormality was reversed by exogenous wild‐type PTPN22 or catalytically dead mutant PTPN22. The R‐to‐W conversion rendered PTPN22 unable to interact with PAD‐4 and suppress citrullination. The C1858T SNP was associated with hypercitrullination in peripheral blood mononuclear cells and a heightened propensity for spontaneous formation of NETs, which is a PAD‐4–dependent process.ConclusionPTPN22 is an inhibitor of PAD‐4 and protein citrullination. This function of PTPN22 is independent of its phosphatase activity but requires R620. Our data not only establish a molecular link between PTPN22 and PAD‐4, but also suggest that the C1858T SNP increases the risk of RA by enhancing protein citrullination and spontaneous formation of NETs.

Từ khóa


Tài liệu tham khảo

10.1007/s11926-011-0193-7

10.1111/j.0105-2896.2009.00853.x

10.1002/bip.22127

10.1002/art.22983

10.1093/rheumatology/keh414

10.1189/jlb.70.1.46

10.1002/jnr.20431

10.1002/art.27439

10.1371/journal.pone.0021314

10.1136/ard.2007.075192

10.1038/ng1206

10.1126/scitranslmed.3005370

10.1083/jcb.200806072

10.1084/jem.20100239

10.1126/scitranslmed.3005580

10.4049/jimmunol.1100450

10.1038/nature12873

10.1086/422827

10.1086/516736

10.1086/468189

10.1038/ng.904

10.1172/JCI66963

10.1002/(SICI)1521-4141(199912)29:12<3845::AID-IMMU3845>3.0.CO;2-U

10.1016/S0301-472X(01)00794-9

10.1038/nsb1101-998

10.1074/jbc.M600498200

10.1038/ni.2958

10.4049/jimmunol.1203363

10.1016/j.immuni.2013.06.013

10.1038/ng1673

10.1016/j.jaut.2008.01.001

10.1371/journal.pone.0086677

10.4049/jimmunol.179.7.4704

10.4049/jimmunol.0713370

10.4049/jimmunol.1102176

10.1111/cei.12362

10.1016/j.coi.2012.07.008

10.4049/jimmunol.1102775

10.1126/science.1092138

10.1186/ar4440

10.4049/jimmunol.180.3.1895

10.1002/glia.10039

10.1371/journal.pone.0033067

10.1186/1471-2199-11-78

10.1136/annrheumdis-2013-203844

10.1073/pnas.1308362110

10.1074/jbc.M110.170290

10.1186/gm301

Thông tin
Thông tin xuất bản

Arthritis and Rheumatology

Tập 67 Số 9

2323-2334

Thông tin tác giả