Protein Phosphatases in Systemic Autoimmunity

Overview

Journal Immunometabolism (Cobham)

Specialty Allergy & Immunology

Date 2025 Feb 13

PMID 39944077

Authors

Wenliang Pan

Maria G Tsokos

Wei Li

George C Tsokos

Affiliations

Soon will be listed here.

Abstract

Protein phosphatases play a critical role in maintaining immune homeostasis by regulating various signaling pathways involved in immune cell activation, differentiation, and function. In the context of systemic autoimmune diseases, dysregulation of phosphatase activity contributes to aberrant immune responses, leading to chronic inflammation and tissue damage. This review explores the role of key phosphatases from the protein serine/threonine phosphatase and protein tyrosine phosphatase families that are implicated in systemic autoimmunity. We discuss their diverse roles in immune cell subsets, the mechanisms by which their dysregulation drives autoimmune pathogenesis, and the therapeutic potential of targeting these enzymes.

References

Chen M, Chuang H, Yeh Y, Chou C, Tan T . Dual-specificity phosphatases 22-deficient T cells contribute to the pathogenesis of ankylosing spondylitis. BMC Med. 2023; 21(1):46. PMC: 9921195. DOI: 10.1186/s12916-023-02745-6. View

Dijkmans B, van Rijthoven A, Goei The H, Boers M, Cats A . Cyclosporine in rheumatoid arthritis. Semin Arthritis Rheum. 1992; 22(1):30-6. DOI: 10.1016/0049-0172(92)90046-g. View

Deng C, Minguela A, Hussain R, Lovett-Racke A, Radu C, Ward E . Expression of the tyrosine phosphatase SRC homology 2 domain-containing protein tyrosine phosphatase 1 determines T cell activation threshold and severity of experimental autoimmune encephalomyelitis. J Immunol. 2002; 168(9):4511-8. DOI: 10.4049/jimmunol.168.9.4511. View

Lorenz U . SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol Rev. 2009; 228(1):342-59. PMC: 2669678. DOI: 10.1111/j.1600-065X.2008.00760.x. View

Li R, Zhang C, Xie F, Zhou X, Hu X, Shi J . Protein Phosphatase 2A Deficiency in Macrophages Increases Foam Cell Formation and Accelerates Atherosclerotic Lesion Development. Front Cardiovasc Med. 2022; 8:745009. PMC: 8803755. DOI: 10.3389/fcvm.2021.745009. View

Zheng H, Qi Y, Hu S, Cao X, Xu C, Yin Z . Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase. Science. 2020; 370(6520). DOI: 10.1126/science.abb5872. View

Arechiga A, Habib T, He Y, Zhang X, Zhang Z, Funk A . Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J Immunol. 2009; 182(6):3343-7. PMC: 2797545. DOI: 10.4049/jimmunol.0713370. View

Sunahori K, Nagpal K, Hedrich C, Mizui M, Fitzgerald L, Tsokos G . The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway.... J Biol Chem. 2013; 288(30):21936-44. PMC: 3724648. DOI: 10.1074/jbc.M113.467266. View

Chen A, Zhou G, Juan T, Colicos S, Cannon J, Meyer C . The dual specificity JKAP specifically activates the c-Jun N-terminal kinase pathway. J Biol Chem. 2002; 277(39):36592-601. DOI: 10.1074/jbc.M200453200. View

10.

Jeanpierre M, Cognard J, Tusseau M, Riller Q, Bui L, Berthelet J . Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus. J Exp Med. 2024; 221(9. PMC: 11259789. DOI: 10.1084/jem.20232337. View

11.

Moron B, Spalinger M, Kasper S, Atrott K, Frey-Wagner I, Fried M . Activation of protein tyrosine phosphatase non-receptor type 2 by spermidine exerts anti-inflammatory effects in human THP-1 monocytes and in a mouse model of acute colitis. PLoS One. 2013; 8(9):e73703. PMC: 3767590. DOI: 10.1371/journal.pone.0073703. View

12.

Spalinger M, Kasper S, Chassard C, Raselli T, Frey-Wagner I, Gottier C . PTPN2 controls differentiation of CD4⁺ T cells and limits intestinal inflammation and intestinal dysbiosis. Mucosal Immunol. 2014; 8(4):918-29. DOI: 10.1038/mi.2014.122. View

13.

Pan W, Sharabi A, Ferretti A, Zhang Y, Burbano C, Yoshida N . PPP2R2D suppresses IL-2 production and Treg function. JCI Insight. 2020; 5(19). PMC: 7566706. DOI: 10.1172/jci.insight.138215. View

14.

Kralova J, Pavliuchenko N, Fabisik M, Ilievova K, Spoutil F, Prochazka J . The receptor-type protein tyrosine phosphatase CD45 promotes onset and severity of IL-1β-mediated autoinflammatory osteomyelitis. J Biol Chem. 2021; 297(4):101131. PMC: 8455366. DOI: 10.1016/j.jbc.2021.101131. View

15.

Vermeren S, Miles K, Chu J, Salter D, Zamoyska R, Gray M . PTPN22 Is a Critical Regulator of Fcγ Receptor-Mediated Neutrophil Activation. J Immunol. 2016; 197(12):4771-4779. PMC: 5136470. DOI: 10.4049/jimmunol.1600604. View

16.

Gu Q, Tung K, Lorenz U . Treg-specific deletion of the phosphatase SHP-1 impairs control of inflammation . Front Immunol. 2023; 14:1139326. PMC: 10060847. DOI: 10.3389/fimmu.2023.1139326. View

17.

Juang Y, Rauen T, Wang Y, Ichinose K, Benedyk K, Tenbrock K . Transcriptional activation of the cAMP-responsive modulator promoter in human T cells is regulated by protein phosphatase 2A-mediated dephosphorylation of SP-1 and reflects disease activity in patients with systemic lupus erythematosus. J Biol Chem. 2010; 286(3):1795-801. PMC: 3023474. DOI: 10.1074/jbc.M110.166785. View

18.

Orru V, Tsai S, Rueda B, Fiorillo E, Stanford S, Dasgupta J . A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum Mol Genet. 2008; 18(3):569-79. PMC: 2722189. DOI: 10.1093/hmg/ddn363. View

19.

Rohan P, Davis P, Moskaluk C, Kearns M, Krutzsch H, Siebenlist U . PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase. Science. 1993; 259(5102):1763-6. DOI: 10.1126/science.7681221. View

20.

Hong S, Lu Y, Chen S, Hsu C, Lu Y, Wang C . Targeting pathogenic macrophages by the application of SHP-1 agonists reduces inflammation and alleviates pulmonary fibrosis. Cell Death Dis. 2023; 14(6):352. PMC: 10249559. DOI: 10.1038/s41419-023-05876-z. View