title: A coding IRAK2 protein variant compromises Toll-like receptor (TLR) signaling and is associated with colorectal cancer survival.
abstract: Within innate immune signaling pathways, interleukin-1 receptor-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors and the interleukin-1 receptor. Although human IRAK4 deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and Toll-like receptor-mediated cytokine induction. This was due to reduced ubiquitination of TRAF6, a key step in signal transduction. IRAK2 rs35060588 occurs in 3-9% of individuals in different ethnic groups, and our studies suggested a genetic association of rs35060588 with colorectal cancer survival. This for the first time implicates human IRAK2 in a human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.
authors: Junior Research Group Toll-like Receptors and Cancer and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors: Hui
authors: H
authors: Wang
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors: Sinead M
authors: SM
authors: Flannery
authors: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors: Sabine
authors: S
authors: Dickhöfer
authors: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors: Stefanie
authors: S
authors: Huhn
authors: Junior Research Group Toll-like Receptors and Cancer and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors: Julie
authors: J
authors: George
authors: Junior Research Group Toll-like Receptors and Cancer and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors: Andriy V
authors: AV
authors: Kubarenko
authors: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors: Jesus
authors: J
authors: Lascorz
authors: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors: Melanie
authors: M
authors: Bevier
authors: Department of Infectious Diseases/Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors: Joschka
authors: J
authors: Willemsen
authors: Junior Research Group Toll-like Receptors and Cancer and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors: Tica
authors: T
authors: Pichulik
authors: Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany,; POPGEN Biobank Project, Christian-Albrechts University, 24105 Kiel, Germany.
authors: Clemens
authors: C
authors: Schafmayer
authors: Department of Infectious Diseases/Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors: Marco
authors: M
authors: Binder
authors: INSERM, Unité 1013 and Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75015 Paris, France.
authors: Bénédicte
authors: B
authors: Manoury
authors: Department of Biomedicine, Aarhus University, Bartholin Building, 8000 Aarhus, Denmark.
authors: Søren R
authors: SR
authors: Paludan
authors: Pfizer-Universidad de Granada-Junta de Andalucía Centre for Genomics and Oncological Research, Avenida de la Ilustración 114, 18016 Granada, Spain,; Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104,; BIOLUPUS Network, European Science Foundation, F-67080 Strasbourg Cedex, France, and.
authors: Marta
authors: M
authors: Alarcon-Riquelme
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors: Andrew G
authors: AG
authors: Bowie
authors: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany,; Center for Primary Health Care Research, Clinical Research Center, Lund University, 20502 Malmö, Sweden.
authors: Asta
authors: A
authors: Försti
authors: Junior Research Group Toll-like Receptors and Cancer and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany,. Electronic address: alexander.weber@uni-tuebingen.de.
authors: Alexander N R
authors: ANR
authors: Weber
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D016328:NF-kappa B; D009363:Neoplasm Proteins; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: Colorectal Cancer; Genetic Variant; Innate Immunity; Interleukin Receptor-associated Kinase (IRAK); Signal Transduction; Single Nucleotide Polymorphism; Toll-like Receptor (TLR)