Abstract
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.
Highlights
Signaling by the IL-36 receptor is poorly characterized
The addition of both IL-36␥ and IL-36RA resulted in reduced IL-6 production relative to cells treated with only IL-36␥, indicating that NCI cells respond to IL-36RA (Fig. 1B)
We sought to establish the requirements for IL-36 receptor (IL-36R) signaling and trafficking and compare the requirements to those exhibited by the IL-1R
Summary
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. Significance: This work defines the requirements for IL-36R signaling and trafficking. 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. 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 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
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