The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity

Immunity. 2013 Jul 25;39(1):111-22. doi: 10.1016/j.immuni.2013.06.013.

Yaya Wang ¹, Iftach Shaked, Stephanie M Stanford, Wenbo Zhou, Julie M Curtsinger, Zbigniew Mikulski, Zachary R Shaheen, Genhong Cheng, Kristy Sawatzke, Amanda M Campbell, Jennifer L Auger, Hatice Bilgic, Fernanda M Shoyama, David O Schmeling, Henry H Balfour Jr, Kiminori Hasegawa, Andrew C Chan, John A Corbett, Bryce A Binstadt, Matthew F Mescher, Klaus Ley, Nunzio Bottini, Erik J Peterson

Affiliations

Affiliation

1 Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.

PMID: 23871208 DOI: 10.1016/j.immuni.2013.06.013

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.

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