Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling.
Bottom Line: Pep(-/-) hematopoietic progenitors demonstrate increased IFNAR signaling, increased IFN-inducible gene expression, and enhanced proliferation and activation compared to Pep(+/+) progenitors in response to IFN-α.In addition, Pep(-/-) mice treated with IFN-α display a profound defect in hematopoiesis, resulting in anemia, thrombocytopenia, and neutropenia when compared to IFN-α-treated Pep(+/+) mice.As SLE patients carrying the PTPN22(C1858T) risk variant have higher serum IFN-α activity, these data provide a molecular basis for how type I IFNs and PTPN22 may cooperate to contribute to lupus-associated cytopenias.
Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.Show MeSH
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Mentions: To further explore the biochemical nature by which PEP regulates IFNAR signaling, we expressed PEP in 3T3 cells that are IFN-α responsive. 3T3 cells expressing transfected PEP demonstrated reduced STAT1 and STAT2 phosphorylation after rIFN-α4 stimulation compared to vector control cDNA-transfected cells (Fig. 6, A and B). The phosphatase activity of PEP was required for maximal reduction of STAT1 phosphorylation because expression of a catalytically inactive PEP(C227S) did not reduce STAT1 phosphorylation to the same extent as wild-type PEP (Fig. 6, C and D). Finally, we investigated whether PEP could co-localize with the IFNAR signaling complex. In 3T3 cells transfected with a Pep cDNA, PEP co-immunoprecipitated with multiple components of the IFNAR signaling complex, including JAK1, TYK2, SOCS1, IFNAR, and STAT1 (Fig. 6 E). Hence, PEP is physically positioned to regulate IFNAR signaling.
Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.