Myddosome assembly and stability controls IL-1 inflammatory signaling

• Applicant: Marcus Taylor, Ph.D.
• Subject Area: Cell Biology ; Biochemistry ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499533619

The cytokine IL-1 is a master regulator of inflammatory responses, driving both beneficial responses like tissue remodeling and pathogen clearance as well as detrimental tissue pathology through its action on a broad range of immune cell types. For example, IL-1 signaling is a major contributor to the pathology associated with rheumatoid arthritis, smoldering multiple myeloma, and type-2 diabetes1. IL-1 signals via the IL-1 receptor (IL-1R), and tight regulation of IL-1 sensing and IL-1R signaling is crucial to the formation of an effective immune response by the host. IL-1 binding to the IL-1 receptor (IL-1R) triggers the assembly of the Myddosome, an oligomeric signaling complex composed of MyD88 and members of the IL-1 Receptor Associated Kinases (IRAKs). Therapeutics that inhibit IL-1 and Myddosome signaling, such as IRAK kinase inhibitors, are promising anti-inflammatory treatments. IL-1 signaling is a dynamic process: the rapid re-localization and assembly of MyD88 and IRAKs at the cell surface is critical for effective IL-1 signaling. However, the current molecular model of IL-1R signal transduction comes from static endpoint assays such as molecular pulldowns, Western blotting, and structural analysis. These assays lack temporal and spatial resolution. Therefore, despite the high relevance to human health, the lack of time-resolved data on the molecular dynamics of Myddosome assembly means the regulatory mechanisms that control IL-1R signaling and inflammation remain poorly understood. Unlike receptor tyrosine kinases (RTKs) or G-protein coupled receptors (GPCRs), IL- 1R has no intrinsic kinase activity or links to secondary messengers. The regulatory mechanisms that control these well characterized signaling receptor families do not apply to IL-1R signaling. In contrast to GPCRs and RTKs, the molecular mechanism of IL-1 signaling has yet to be investigated by high spatial-temporal resolution microscopy. The overarching goal of this proposal is to understand the molecular mechanisms that control IL-1 activation of Myddosome assembly and signaling. These regulatory mechanisms are critical to ensuring a decisive but controlled inflammatory response. In a departure from previous studies on IL-1 and Myddosome signaling, this research proposal will use high spatial-temporal resolution microscopy to investigate the molecular mechanisms of IL-1R signaling in live cells. This approach is innovative because this methodology can unpack the intricate molecular dynamics that control IL-1R signaling. This is important because it will potentially reveal the critical steps in IL-1 signaling that can be therapeutically targeted and discover how anti-inflammatory therapeutics, currently in clinical trials2, disrupt this central regulatory node of inflammation. Furthermore, understanding the molecular dynamics of IL-1R signaling is significant to understanding the diversity and basic biology of cell signaling mechanisms.

• DFG Programme: Research Grants