IRAK4 autophosphorylation functions as a molecular switch to regulate death domain assembly and Myddosome maturation

IRAK4 autophosphorylation functions as a molecular switch to regulate death domain assembly and Myddosome maturation | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article IRAK4 autophosphorylation functions as a molecular switch to regulate death domain assembly and Myddosome maturation Marcus Taylor, Niranjan Srikanth, Rafael Deliz-Aguirre, Deepika Kumari Gola, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8872830/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The organization of signaling proteins into multi-component complexes is essential for innate immune responses and is often achieved through the oligomerization of death domains (DDs). The Myddosome, composed of MyD88 and IRAK family kinases, exemplifies this mechanism. However, how DDs assemble in an ordered and regulated manner to form Myddosomes to control signaling output remains unknown. Here, we show that IRAK4 kinase activity and autophosphorylation are required for IRAK4:IRAK1 heterotypic DD interactions. We discovered that IRAK1 is autoinhibited by its kinase domain, and IRAK4 phosphorylation relieves this inhibition, enabling IRAK1 DD incorporation into Myddosomes. This phosphorylation-dependent switch similarly controls IRAK2/3 incorporation. Thus, IRAK4 autophosphorylation acts as an energy-dependent molecular switch that integrates phosphorylation with protein oligomerization to drive Myddosome maturation and signal transduction. This mechanism demonstrates how enzymatic activity can impose temporal and spatial control over macromolecular assembly to ensure directional and context-dependent inflammatory signaling. Biological sciences/Cell biology/Cell signalling Biological sciences/Biochemistry/Kinases Full Text Additional Declarations Yes there is potential Competing Interest. MJT has research projects sponsored by Kymera Therapeutics and is a scientific advisory board member at RheumaGen. Supplementary Files SupplementaryMovie1IRAK4WTIRAK1WTvsIRAK4DelKDIRAK1WT1.mp4 Supplementary Movie 1 SupplementaryMovie2IRAK4WTIRAK1WTvsIRAK4WTIRAK1DelKD1.mp4 Supplementary Movie 2 SupplementaryMovie3IRAK4DelKDIRAK2WTandIRAK4DelKDIRAK3WT.mp4 Supplementary Movie 3 SupplementaryMovie4IRAK4WTIRAK2DelKDandIRAK4WTIRAK3DelKD.mp4 Supplementary Movie 4 SupplementaryMovie5.mp4 Supplementary Movie 5 SupplementaryMovie6.mp4 Supplementary Movie 6 SupplementaryMovie7.mp4 Supplementary Movie 7 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

Related documents

• WEE1 stabilizes MYC to promote therapeutic resistance in esophageal adenocarcinoma#260119
• Interactome Mapping of the Phosphatidylinositol 3-Kinase-Mammalian Target of Rapamycin Pathway Identifies Deformed Epidermal Autoregulatory Factor-1 as a New Glycogen Synthase Kinase-3 Interactor#257479
• Replication Data for: Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation#274888
• Survey of the human proteostasis network: the ubiquitin-proteasome system#1110881
• Characterization of the Mechanisms of Resistance to Azacitidine#1137313