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      TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo

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          Abstract

          Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive ( Tyk2 K923E ) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein’s stability. An inhibitory function was only observed upon over-expression of TYK2 K923E in vitro. Tyk2 K923E mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors.

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          Most cited references53

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          Recognition and processing of ubiquitin-protein conjugates by the proteasome.

          The proteasome is an intricate molecular machine, which serves to degrade proteins following their conjugation to ubiquitin. Substrates dock onto the proteasome at its 19-subunit regulatory particle via a diverse set of ubiquitin receptors and are then translocated into an internal chamber within the 28-subunit proteolytic core particle (CP), where they are hydrolyzed. Substrate is threaded into the CP through a narrow gated channel, and thus translocation requires unfolding of the substrate. Six distinct ATPases in the regulatory particle appear to form a ring complex and to drive unfolding as well as translocation. ATP-dependent, degradation-coupled deubiquitination of the substrate is required both for efficient substrate degradation and for preventing the degradation of the ubiquitin tag. However, the proteasome also contains deubiquitinating enzymes (DUBs) that can remove ubiquitin before substrate degradation initiates, thus allowing some substrates to dissociate from the proteasome and escape degradation. Here we examine the key elements of this molecular machine and how they cooperate in the processing of proteolytic substrates.
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            Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.

            Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.
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              A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                18 June 2012
                : 7
                : 6
                : e39141
                Affiliations
                [1 ]Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
                [2 ]Biomodels Austria, University of Veterinary Medicine, Vienna, Austria
                [3 ]Genetic Reprogramming Group Agricultural Biotechnology Center, Gödöllö, Hungary
                [4 ]Department for Agrobiotechnology IFA Tulln, University of Natural Resources and Life Sciences, Vienna, Austria
                [5 ]Institute of Laboratory Animal Science, University of Veterinary Medicine, Vienna, Austria
                [6 ]Molecular Animal Biotechnology Laboratory, Szent Istvan University, Gödöllö, Hungary
                [7 ]BioTalentum Ltd., Gödöllö, Hungary
                National Jewish Health and University of Colorado School of Medicine, United States of America
                Author notes

                Conceived and designed the experiments: MK BS MM. Performed the experiments: MPM CS CL JK BW CG ITK. Analyzed the data: MPM CS BW BS. Contributed reagents/materials/analysis tools: ITK SM AD TR TK. Wrote the paper: NRL BS MM.

                Article
                PONE-D-12-03580
                10.1371/journal.pone.0039141
                3377589
                22723949
                81c148b6-1766-4c55-9693-269aa2526880
                Prchal-Murphy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 31 January 2012
                : 20 May 2012
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Genetics
                Gene Function
                Immunology
                Immunity
                Immune Defense
                Innate Immunity
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Signal Transduction

                Uncategorized
                Uncategorized

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