Intracellular trafficking of Interleukin-1 receptor I requires Tollip

Interleukin-1 receptor (IL-1 RI) is a master regulator of inflammation and innate immunity [1]. When triggered by IL-1 P, IL-1 RI aggregates with IL-1 R-associated protein (IL-1RAcP) and forms a membrane proximal signalosome that potently activates downstream signaling cascades. IL-1 p also rapidly triggers endocytosis of IL-1RI [2, 3]. Although internalization of IL-1RI significantly impacts signaling [4], very little is known about trafficking of IL-1RI and therefore about precisely how endocytosis modulates the overall cellular response to IL-1 P. Upon internalization, activated receptors are often sorted through endosomes and delivered to lysosomes for degradation. This is a highly regulated process that requires ubiquitination of cargo proteins as well as protein-sorting complexes that specifically recognize ubiquitinated cargo [5]. Here, we show that IL-1 beta induces ubiquitination of IL-1RI and that via these attached ubiquitin groups, IL-1RI interacts with the ubiquitin-binding protein Tollip [6]. By using an assay to follow trafficking of IL-1 RI from the cell surface to late endosomes and lysosomes, we demonstrate that Tollip is required for sorting of IL-1 RI at late endosomes. In Tollip-deficient cells and cells expressing only mutated Tollip (incapable of binding IL-1RI and ubiquitin), IL-1RI accumulates on late endosomes and is not efficiently degraded. Furthermore, we show that IL-1RI interacts with Tom1, an ubiquitin-, clathrin-, and Tollip-binding protein [7, 8), and that Tom1 knockdown also results in the accumulation of IL-1 RI at late endosomes. Our findings suggest that Tollip functions as an endosomal adaptor linking IL-1 RI, via Tom1, to the endosomal degradation machinery.