A Natural Mutation in the Tyk2 Pseudokinase Domain Underlies Altered Susceptibility of B10.Q/J Mice to Infection and Autoimmunity

The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but markedly resistant to induction of autoimmune arthritis. We have previously shown that the B10.Q/J phenotype is controlled by a single recess...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 100; no. 20; pp. 11594 - 11599
Main Authors Shaw, Michael H., Boyartchuk, Victor, Wong, Sandy, Karaghiosoff, Marina, Ragimbeau, Josiane, Pellegrini, Sandra, Muller, Mathias, Dietrich, William F., Yap, George S.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 30.09.2003
National Acad Sciences
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Abstract The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but markedly resistant to induction of autoimmune arthritis. We have previously shown that the B10.Q/J phenotype is controlled by a single recessive locus and is associated with lymphocyte hyporesponsiveness to IL-12. Using genetic approaches, we have now localized the B10.Q/J locus to chromosome 9 and established its identity as Tyk2, a Janus kinase essential for IL-12 and IFN-α/β cytokine signaling. The B10.Q/J Tyk2 gene contained a single missense mutation resulting in a nonconservative amino acid substitution (E775K) in an invariant motif of the pseudokinase (Janus kinase homology 2) domain. This mutation appeared to result in the absence of the B10.Q/J-encoded Tyk2 protein, despite presence of Tyk2-specific transcripts. Phenotypically, B10.Q/J cells were indistinguishable from Tyk2-deficient cells, showing impaired signaling and biologic responses to IL-12, IL-23, and type I IFNs. The analogous E782K mutant of human Tyk2 failed to restore IFN-α responsiveness in Tyk2 null 11,1 cells. Our results indicate a crucial role for Tyk2 in T helper 1-mediated protective and pathogenic immune responses. An additional implication of our findings is that naturally occurring mutations in the Tyk2 gene may underlie altered susceptibilities to infectious or autoimmune diseases in human and animal populations.
AbstractList The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but markedly resistant to induction of autoimmune arthritis. We have previously shown that the B10.Q/J phenotype is controlled by a single recessive locus and is associated with lymphocyte hyporesponsiveness to IL-12. Using genetic approaches, we have now localized the B10.Q/J locus to chromosome 9 and established its identity as Tyk2, a Janus kinase essential for IL-12 and IFN-α/β cytokine signaling. The B10.Q/J Tyk2 gene contained a single missense mutation resulting in a nonconservative amino acid substitution (E775K) in an invariant motif of the pseudokinase (Janus kinase homology 2) domain. This mutation appeared to result in the absence of the B10.Q/J-encoded Tyk2 protein, despite presence of Tyk2-specific transcripts. Phenotypically, B10.Q/J cells were indistinguishable from Tyk2-deficient cells, showing impaired signaling and biologic responses to IL-12, IL-23, and type I IFNs. The analogous E782K mutant of human Tyk2 failed to restore IFN-α responsiveness in Tyk2 null 11,1 cells. Our results indicate a crucial role for Tyk2 in T helper 1-mediated protective and pathogenic immune responses. An additional implication of our findings is that naturally occurring mutations in the Tyk2 gene may underlie altered susceptibilities to infectious or autoimmune diseases in human and animal populations.
The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but markedly resistant to induction of autoimmune arthritis. We have previously shown that the B10.Q/J phenotype is controlled by a single recessive locus and is associated with lymphocyte hyporesponsiveness to IL-12. Using genetic approaches, we have now localized the B10.Q/J locus to chromosome 9 and established its identity as Tyk2 , a Janus kinase essential for IL-12 and IFN-α/β cytokine signaling. The B10.Q/J Tyk2 gene contained a single missense mutation resulting in a nonconservative amino acid substitution (E775K) in an invariant motif of the pseudokinase (Janus kinase homology 2) domain. This mutation appeared to result in the absence of the B10.Q/J-encoded Tyk2 protein, despite presence of Tyk2 -specific transcripts. Phenotypically, B10.Q/J cells were indistinguishable from Tyk2 -deficient cells, showing impaired signaling and biologic responses to IL-12, IL-23, and type I IFNs. The analogous E782K mutant of human Tyk2 failed to restore IFN-α responsiveness in Tyk2 null 11,1 cells. Our results indicate a crucial role for Tyk2 in T helper 1-mediated protective and pathogenic immune responses. An additional implication of our findings is that naturally occurring mutations in the Tyk2 gene may underlie altered susceptibilities to infectious or autoimmune diseases in human and animal populations.
The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but markedly resistant to induction of autoimmune arthritis. We have previously shown that the B10.Q/J phenotype is controlled by a single recessive locus and is associated with lymphocyte hyporesponsiveness to IL-12. Using genetic approaches, we have now localized the B10.Q/J locus to chromosome 9 and established its identity as Tyk2, a Janus kinase essential for IL-12 and IFN- alpha / beta cytokine signaling. The B10.Q/J Tyk2 gene contained a single missense mutation resulting in a nonconservative amino acid substitution (E775K) in an invariant motif of the pseudokinase (Janus kinase homology 2) domain. This mutation appeared to result in the absence of the B10.Q/J-encoded Tyk2 protein, despite presence of Tyk2-specific transcripts. Phenotypically, B10.Q/J cells were indistinguishable from Tyk2-deficient cells, showing impaired signaling and biologic responses to IL-12, IL-23, and type I IFNs. The analogous E782K mutant of human Tyk2 failed to restore IFN- alpha responsiveness in Tyk2 null 11,1 cells. Our results indicate a crucial role for Tyk2 in T helper 1-mediated protective and pathogenic immune responses. An additional implication of our findings is that naturally occurring mutations in the Tyk2 gene may underlie altered susceptibilities to infectious or autoimmune diseases in human and animal populations.
The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but markedly resistant to induction of autoimmune arthritis. We have previously shown that the B10.Q/J phenotype is controlled by a single recessive locus and is associated with lymphocyte hyporesponsiveness to IL-12. Using genetic approaches, we have now localized the B10.Q/J locus to chromosome 9 and established its identity as Tyk2, a Janus kinase essential for IL-12 and IFN-{alpha}/{beta} cytokine signaling. The B10.Q/J Tyk2 gene contained a single missense mutation resulting in a nonconservative amino acid substitution (E775K) in an invariant motif of the pseudokinase (Janus kinase homology 2) domain. This mutation appeared to result in the absence of the B10.Q/J-encoded Tyk2 protein, despite presence of Tyk2-specific transcripts. Phenotypically, B10.Q/J cells were indistinguishable from Tyk2-deficient cells, showing impaired signaling and biologic responses to IL-12, IL-23, and type I IFNs. The analogous E782K mutant of human Tyk2 failed to restore IFN-{alpha} responsiveness in Tyk2 null 11,1 cells. Our results indicate a crucial role for Tyk2 in T helper 1-mediated protective and pathogenic immune responses. An additional implication of our findings is that naturally occurring mutations in the Tyk2 gene may underlie altered susceptibilities to infectious or autoimmune diseases in human and animal populations. [PUBLICATION ABSTRACT]
Author Shaw, Michael H.
Ragimbeau, Josiane
Karaghiosoff, Marina
Boyartchuk, Victor
Dietrich, William F.
Yap, George S.
Wong, Sandy
Pellegrini, Sandra
Muller, Mathias
AuthorAffiliation Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912; † Department of Genetics and ¶ Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; ‡ Institute of Animal Breeding and Genetics, Veterinary University of Vienna, A-1210 Vienna, Austria; and § Unité de Signalisation des Cytokines, Institut Pasteur, 75724 Paris Cedex 16, France
AuthorAffiliation_xml – name: Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912; † Department of Genetics and ¶ Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; ‡ Institute of Animal Breeding and Genetics, Veterinary University of Vienna, A-1210 Vienna, Austria; and § Unité de Signalisation des Cytokines, Institut Pasteur, 75724 Paris Cedex 16, France
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  surname: Shaw
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To whom correspondence should be addressed. E-mail: george_yap@brown.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: Stat, signal transducer and activator of transcription; Jak, Janus kinase; JH, Jaks homology; LOD, logarithm of odds.
Edited by William E. Paul, National Institutes of Health, Bethesda, MD, and approved July 30, 2003
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Snippet The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but...
The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but...
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SubjectTerms Animals
Autoimmune diseases
Autoimmunity - genetics
Biological Sciences
Cell lines
Gene Expression Regulation, Enzymologic
Genes
Genetic Complementation Test
Genetic loci
Genetic mutation
Genetic Predisposition to Disease
Human genetics
Immunology
Infection - genetics
Infections
Lymphocytes
Medical genetics
Mice
Mice, Inbred BALB C
Mutagenesis
Mutation
Parasites
Phenotypes
Point Mutation
Protein-Tyrosine Kinases
Proteins - genetics
Proteins - immunology
Rodents
T lymphocytes
TYK2 Kinase
Title A Natural Mutation in the Tyk2 Pseudokinase Domain Underlies Altered Susceptibility of B10.Q/J Mice to Infection and Autoimmunity
URI https://www.jstor.org/stable/3147837
http://www.pnas.org/content/100/20/11594.abstract
https://www.ncbi.nlm.nih.gov/pubmed/14500783
https://www.proquest.com/docview/201285293
https://search.proquest.com/docview/18882893
https://pubmed.ncbi.nlm.nih.gov/PMC208803
Volume 100
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