uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Two rare disease-associated tyk2 variants are catalytically impaired but signaling competent
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
Show others and affiliations
2013 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, no 5, 2335-2344 p.Article in journal (Refereed) Published
Abstract [en]

Tyk2 belongs to the Janus protein tyrosine kinase family and is involved in signaling of immunoregulatory cytokines (type I and III IFNs, IL-6, IL-10, and IL-12 families) via its interaction with shared receptor subunits. Depending on the receptor complex, Tyk2 is coactivated with either Jak1 or Jak2, but a detailed molecular characterization of the interplay between the two enzymes is missing. In human populations, the Tyk2 gene presents high levels of genetic diversity with >100 nonsynonymous variants being detected. In this study, we characterized two rare Tyk2 variants, I684S and P1104A, which have been associated with susceptibility to autoimmune disease. Specifically, we measured their in vitro catalytic activity and their ability to mediate Stat activation in fibroblasts and genotyped B cell lines. Both variants were found to be catalytically impaired but rescued signaling in response to IFN-α/β, IL-6, and IL-10. These data, coupled with functional study of an engineered Jak1 P1084A, support a model of nonhierarchical activation of Janus kinases in which one catalytically competent Jak is sufficient for signaling provided that its partner behaves as proper scaffold, even if inactive. Through the analysis of IFN-α and IFN-γ signaling in cells with different Jak1 P1084A levels, we also illustrate a context in which a hypomorphic Jak can hamper signaling in a cytokine-specific manner. Given the multitude of Tyk2-activating cytokines, the cell context-dependent requirement for Tyk2 and the catalytic defect of the two disease-associated variants studied in this paper, we predict that these alleles are functionally significant in complex immune disorders.

Place, publisher, year, edition, pages
2013. Vol. 190, no 5, 2335-2344 p.
Keyword [en]
tyrosin kinase 2, genetic variants
National Category
Rheumatology and Autoimmunity
Research subject
URN: urn:nbn:se:uu:diva-196290DOI: 10.4049/jimmunol.1203118ISI: 000315089100048PubMedID: 23359498OAI: oai:DiVA.org:uu-196290DiVA: diva2:609683
Available from: 2013-03-06 Created: 2013-03-06 Last updated: 2013-06-12Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Eloranta, Maija-LeenaRönnblom, Lars
By organisation
In the same journal
Journal of Immunology
Rheumatology and Autoimmunity

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 172 hits
ReferencesLink to record
Permanent link

Direct link