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IRAK4 Kinase Activity Is Redundant for Interleukin-1 (IL-1) Receptor-associated Kinase Phosphorylation and IL-1 Responsiveness
Open accessAbstract
Interleukin-1 (IL-1) stimulation leads to the recruitment of interleukin-1 receptor-associated kinase (IRAK) to the IL-1 receptor, where IRAK is phosphorylated, ubiquitinated, and eventually degraded. Kinase-inactive mutant IRAK is still phosphorylated in response to IL-1 stimulation when it is transfected into IRAK-deficient cells, suggesting that there must be an IRAK kinase in the pathway. The fact that IRAK4, another IRAK family member necessary for the IL-1 pathway, is able to phosphorylate IRAK in vitro suggests that IRAK4 might be the IRAK kinase. However, we now found that the IRAK4 kinase-inactive mutant had the same ability as the wild-type IRAK4 in restoring IL-1-mediated signaling in human IRAK4-deficient cells, including NFkappaB-dependent reporter gene expression, the activation of NFkappaB and JNK, and endogenous IL-8 gene expression. These results strongly indicate that the kinase activity of human IRAK4 is not necessary for IL-1 signaling. Furthermore, we showed that the kinase activity of IRAK4 was not necessary for IL-1-induced IRAK phosphorylation, suggesting that IRAK phosphorylation can probably be achieved either by autophosphorylation or by trans-phosphorylation through IRAK4. In support of this, only the impairment of the kinase activity of both IRAK and IRAK4 efficiently abolished the IL-1 pathway, demonstrating that the kinase activity of IRAK and IRAK4 is redundant for IL-1-mediated signaling. Moreover, consistent with the fact that IRAK4 is a necessary component of the IL-1 pathway, we found that IRAK4 was required for the efficient recruitment of IRAK to the IL-1 receptor complex.
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“Particularly for IRAK4, its scaffolding role in Toll-like receptor (TLR) signalling around the myddosome is established165,172”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [172]
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Metadata
- Authors
- Qin, J., Jiang, Z., Qian, Y., Casanova, J.-L., & Li, X.
- Affiliations
- Cleveland State University (US)
- Cleveland Clinic (US)
- Inserm (FR)
- Corresponding author
- Li, Xiaoxia
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-06
- Volume
- 279
- Issue
- 25
- Pages
- 26748-26753
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1964985092
- Cited by
- 110
- References
- 27
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 8 · 2017: 2 · 2016: 4 · 2015: 1 · 2014: 6 · 2013: 2 · 2012: 1
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM 60020, R01GM060020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Keywords
- IRAK4, IRAK, IL-1 signaling, IL-1 receptor, kinase redundancy, transphosphorylation, autophosphorylation, NF-κB activation, JNK activation, IL-8 expression
- MeSH terms
- Cell Line, Dose-Response Relationship, Drug, Enzyme Activation, Fibroblasts, Genetic Complementation Test, Humans, Interleukin-1, Luciferases, Models, Biological, Mutation, Phosphorylation, Plasmids, Precipitin Tests, Time Factors, Transfection, Blotting, Northern, Blotting, Western, Interleukin-8, NF-kappa B, Receptors, Interleukin-1, Phosphotransferases (Alcohol Group Acceptor), Genes, Reporter, E-Selectin, Mitogen-Activated Protein Kinase Kinases, Ubiquitin, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Interleukin-1 Receptor-Associated Kinases
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