Regulation of IRAK-1 activation by its C-terminal domain |
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| Authors: | Thao Nguyen Dominic De Nardo Paul Masendycz John A Hamilton Glen M Scholz |
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| Institution: | 3. Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden;4. Department of Nanobioscience, SUNY Polytechnic Institute, Albany, New York 12203;5. Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago, Christchurch 8011, New Zealand;3. National Center for Protein Sciences · Beijing, Beijing, 102206, China;;4. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing, 102206, China;;5. Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458;;6. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232;2. Redox Biology Group, UHI, Inverness, IV2 3JH, UK;3. Inflammation and Remodeling Research Unit, Pfizer Research, Cambridge, Massachusetts 02140;4. Global Biological Technology, Pfizer Research, Cambridge, Massachusetts 02140;5. Pfizer Chemical Technologies Section, Pearl River, New York 10965;6. St. Giles Laboratory of Human Genetics of Infectious Diseases Howard Hughes Medical Institute, Rockefeller University, New York, New York 10065;12. Pediatric Hematology-Immunology Unit, Assistance Publique Hôpitaux de Paris, Necker Hospital, Paris 75015, France;8. Laboratory of Human Genetics of Infectious Diseases, Imagine Institute, Assistance Publique Hôpitaux de Paris, Necker Hospital, Paris 75015, France;9. Study Center for Primary Immunodeficiencies, Assistance Publique Hôpitaux de Paris, Necker Hospital, Paris 75015, France;10. University of Paris at Descartes, Paris 75006, France |
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| Abstract: | Macrophages are important mediators of the immune response to infection by virtue of their ability to secrete cytokines that trigger inflammation. Toll-like receptors (TLRs) are largely responsible for meditating the activation of macrophages by pathogens. IRAK-1 is a proximal protein kinase in TLR signalling pathways and hence its activation must be tightly regulated. However, the mechanisms which control the activation of IRAK-1 are poorly understood. IRAK-1 contains a death domain at its N-terminus that mediates its interaction with other death domain containing proteins, a central Ser/Thr kinase domain, and a C-terminal domain that contains binding motifs for TRAF6. We show here that deletion of the death domain or the majority of the C-terminal domain markedly enhanced the capacity of IRAK-1 to activate NF-κB in a TLR-independent manner in RAW 264.7 macrophages. Furthermore, the C-terminal truncation mutant spontaneously oligomerised and formed complexes with the negative regulator IRAK-M in the absence of TLR activation. In contrast to the binding of IRAK-M to IRAK-1, the death domain of IRAK-1 was not required for the interaction of IRAK-4 with IRAK-1. On the basis of these results we propose a model in which IRAK-1 is held in a closed, inactive conformation via an intramolecular mechanism involving its C-terminal domain and possibly the death domain. Phosphorylation of IRAK-1 by IRAK-4 in response to TLR activation may then release IRAK-1 from the inhibitory constraint exerted by its C-terminal domain. |
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