A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival.

Hui Wang; Sinead M Flannery; Sabine Dickhöfer; Stefanie Huhn; Julie George; Andriy V Kubarenko; Jesus Lascorz; Melanie Bevier; Joschka Willemsen; Tica Pichulik; Clemens Schafmayer; Marco Binder; Benedicte Manoury; Søren R Paludan; Marta Alarcon Riquelme; Andrew G Bowie; Asta Försti; Alexander N R Weber

doi:10.1074/jbc.M113.492934

A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival.

Hui Wang, Sinead M Flannery, Sabine Dickhöfer, Stefanie Huhn, Julie George, Andriy V Kubarenko, Jesus Lascorz, Melanie Bevier, Joschka Willemsen, Tica Pichulik, Clemens Schafmayer, Marco Binder, Benedicte Manoury, Søren R Paludan, Marta Alarcon Riquelme, Andrew G Bowie, Asta Försti, Alexander N R Weber

Research output: Contribution to journal › Article › peer-review

Abstract

Within innate immune signaling pathways, Interleukin-1 receptor (IL-1R&)-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors (TLR) and the IL-1R. Whereas 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 TLR-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 uncovered a significant genetic association of rs35060588 with colorectal cancer survival. This for the first time firmly implicates human IRAK2 in human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.

Original language	English
Pages (from-to)	23123-23131
Journal	Journal of Biological Chemistry
Volume	289
Issue number	33
DOIs	https://doi.org/10.1074/jbc.M113.492934
Publication status	Published - 2014

Subject classification (UKÄ)

Public Health, Global Health, Social Medicine and Epidemiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1074/jbc.M113.492934

http://www.ncbi.nlm.nih.gov/pubmed/24973222?dopt=Abstract

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Wang, H., Flannery, S. M., Dickhöfer, S., Huhn, S., George, J., Kubarenko, A. V., Lascorz, J., Bevier, M., Willemsen, J., Pichulik, T., Schafmayer, C., Binder, M., Manoury, B., Paludan, S. R., Alarcon Riquelme, M., Bowie, A. G., Försti, A., & Weber, A. N. R. (2014). A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival. Journal of Biological Chemistry, 289(33), 23123-23131. https://doi.org/10.1074/jbc.M113.492934

@article{18c52331d4ae4ccc8ce91dc8bb8463e6,

title = "A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival.",

abstract = "Within innate immune signaling pathways, Interleukin-1 receptor (IL-1R&)-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors (TLR) and the IL-1R. Whereas 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 TLR-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 uncovered a significant genetic association of rs35060588 with colorectal cancer survival. This for the first time firmly implicates human IRAK2 in human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.",

author = "Hui Wang and Flannery, {Sinead M} and Sabine Dickh{\"o}fer and Stefanie Huhn and Julie George and Kubarenko, {Andriy V} and Jesus Lascorz and Melanie Bevier and Joschka Willemsen and Tica Pichulik and Clemens Schafmayer and Marco Binder and Benedicte Manoury and Paludan, {S{\o}ren R} and {Alarcon Riquelme}, Marta and Bowie, {Andrew G} and Asta F{\"o}rsti and Weber, {Alexander N R}",

year = "2014",

doi = "10.1074/jbc.M113.492934",

language = "English",

volume = "289",

pages = "23123--23131",

journal = "Journal of Biological Chemistry",

issn = "1083-351X",

publisher = "American Society for Biochemistry and Molecular Biology",

number = "33",

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Wang, H, Flannery, SM, Dickhöfer, S, Huhn, S, George, J, Kubarenko, AV, Lascorz, J, Bevier, M, Willemsen, J, Pichulik, T, Schafmayer, C, Binder, M, Manoury, B, Paludan, SR, Alarcon Riquelme, M, Bowie, AG, Försti, A & Weber, ANR 2014, 'A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival.', Journal of Biological Chemistry, vol. 289, no. 33, pp. 23123-23131. https://doi.org/10.1074/jbc.M113.492934

TY - JOUR

T1 - A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival.

AU - Wang, Hui

AU - Flannery, Sinead M

AU - Dickhöfer, Sabine

AU - Huhn, Stefanie

AU - George, Julie

AU - Kubarenko, Andriy V

AU - Lascorz, Jesus

AU - Bevier, Melanie

AU - Willemsen, Joschka

AU - Pichulik, Tica

AU - Schafmayer, Clemens

AU - Binder, Marco

AU - Manoury, Benedicte

AU - Paludan, Søren R

AU - Alarcon Riquelme, Marta

AU - Bowie, Andrew G

AU - Försti, Asta

AU - Weber, Alexander N R

PY - 2014

Y1 - 2014

N2 - Within innate immune signaling pathways, Interleukin-1 receptor (IL-1R&)-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors (TLR) and the IL-1R. Whereas 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 TLR-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 uncovered a significant genetic association of rs35060588 with colorectal cancer survival. This for the first time firmly implicates human IRAK2 in human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.

AB - Within innate immune signaling pathways, Interleukin-1 receptor (IL-1R&)-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors (TLR) and the IL-1R. Whereas 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 TLR-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 uncovered a significant genetic association of rs35060588 with colorectal cancer survival. This for the first time firmly implicates human IRAK2 in human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.

U2 - 10.1074/jbc.M113.492934

DO - 10.1074/jbc.M113.492934

M3 - Article

C2 - 24973222

SN - 1083-351X

VL - 289

SP - 23123

EP - 23131

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 33

ER -

A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival.

Abstract

Subject classification (UKÄ)

UN SDGs

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