Signal Transduction and Intracellular Trafficking by the Interleukin 36 Receptor

Improper signaling of the IL-36 receptor (IL-36R), a member of the IL-1 receptor family, has been associated with various inflammation-associated diseases. However, the requirements for IL-36R signal transduction remain poorly characterized. This work seeks to define the requirements for IL-36R signaling and intracellular trafficking. In the absence of cognate agonists, IL-36R was endocytosed and recycled to the plasma membrane. In the presence of IL-36, IL-36R increased accumulation in LAMP1+ lysosomes. Endocytosis predominantly used a clathrin-mediated pathway, and the accumulation of the IL-36R in lysosomes did not result in increased receptor turnover. The ubiquitin-binding Tollip protein contributed to IL-36R signaling and increased the accumulation of both subunits of the IL-36R. Background: Signaling by the IL-36 receptor is poorly characterized. Results: Activation of IL-36R signaling is coupled with its endocytosis to lysosomes. Tollip mediates IL-1 receptor turnover and increases the accumulation of IL-36R. Conclusion: IL-36R signaling has differences in signaling from the IL-1R. Significance: This work defines the requirements for IL-36R signaling and trafficking.