title: The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity.
abstract: Immune cells sense microbial products through Toll-like receptors (TLR), which trigger host defense responses including type 1 interferons (IFNs) secretion. A coding polymorphism in the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is a susceptibility allele for human autoimmune and infectious disease. We report that Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells. Ptpn22 promoted host antiviral responses and was critical for TLR agonist-induced, type 1 IFN-dependent suppression of inflammation in colitis and arthritis. PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination. The disease-associated PTPN22W variant failed to promote TRAF3 ubiquitination, type 1 IFN upregulation, and type 1 IFN-dependent suppression of arthritis. The findings establish a candidate innate immune mechanism of action for a human autoimmunity "risk" gene in the regulation of host defense and inflammation.
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Yaya
authors.initials: Y
authors.lastname: Wang
authors.forename: Iftach
authors.initials: I
authors.lastname: Shaked
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Stanford
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhou
authors.forename: Julie M
authors.initials: JM
authors.lastname: Curtsinger
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Mikulski
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Shaheen
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Kristy
authors.initials: K
authors.lastname: Sawatzke
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Campbell
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Auger
authors.forename: Hatice
authors.initials: H
authors.lastname: Bilgic
authors.forename: Fernanda M
authors.initials: FM
authors.lastname: Shoyama
authors.forename: David O
authors.initials: DO
authors.lastname: Schmeling
authors.forename: Henry H
authors.initials: HH
authors.lastname: Balfour
authors.forename: Kiminori
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chan
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Binstadt
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Mescher
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Peterson
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D016264:Dextran Sulfate / Q000276:immunology; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000235:genetics / Q000276:immunology*; D015151:Immunoblotting; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology
chemical_list: D007370:Interferon Type I; D048008:TNF Receptor-Associated Factor 3; D051193:Toll-Like Receptors; D016264:Dextran Sulfate; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse