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

Wang, Hui ; Flannery, Sinead M ; Dickhöfer, Sabine ; Huhn, Stefanie ; George, Julie ; Kubarenko, Andriy V ; Lascorz, Jesus ; Bevier, Melanie LU ; Willemsen, Joschka and Pichulik, Tica , et al. (2014) In Journal of Biological Chemistry 289(33). p.23123-23131
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
289
issue
33
pages
23123 - 23131
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • pmid:24973222
  • wos:000341017200049
  • scopus:84905981869
  • pmid:24973222
ISSN
1083-351X
DOI
10.1074/jbc.M113.492934
language
English
LU publication?
yes
id
18c52331-d4ae-4ccc-8ce9-1dc8bb8463e6 (old id 4523718)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24973222?dopt=Abstract
date added to LUP
2016-04-01 10:32:34
date last changed
2022-01-26 00:16:56
@article{18c52331-d4ae-4ccc-8ce9-1dc8bb8463e6,
  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       = {{Wang, Hui and Flannery, Sinead M and Dickhöfer, Sabine and Huhn, Stefanie and George, Julie and Kubarenko, Andriy V and Lascorz, Jesus and Bevier, Melanie and Willemsen, Joschka and Pichulik, Tica and Schafmayer, Clemens and Binder, Marco and Manoury, Benedicte and Paludan, Søren R and Alarcon Riquelme, Marta and Bowie, Andrew G and Försti, Asta and Weber, Alexander N R}},
  issn         = {{1083-351X}},
  language     = {{eng}},
  number       = {{33}},
  pages        = {{23123--23131}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival.}},
  url          = {{http://dx.doi.org/10.1074/jbc.M113.492934}},
  doi          = {{10.1074/jbc.M113.492934}},
  volume       = {{289}},
  year         = {{2014}},
}