Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor

Abstract

Interleukin-1 (IL-1) is a proinflammatory cytokine that elicits its pleiotropic effects through activation of the transcription factors NF-kappaB and AP-1. Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1beta treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip-IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs). As overexpression of Tollip results in impaired NF-kappaB activation, we conclude that Tollip is an important constituent of the IL-1R signalling pathway.

NF-κB and the immune response

“…For example, IRAK-M (IRAK3) inhibits signaling to TRAF6 by fixing IRAK-1/4 to the TLR/MyD88 signaling complex; irakm À/À knockouts exhibit enhanced signaling to NF-kB (Kobayashi et al, 2002). Tollip, an adapter protein constitutively associated with IRAK, is phosphorylated and dissociates following IRAK4 activation (Burns et al, 2000;Zhang and Ghosh, 2002). Negative regulation of TLR signaling by Tollip in the intestinal epithelium may prevent inflammatory responses to commensal bacteria (Melmed et al, 2003).…”

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

“…MyD88 also contains a death domain that facilitates the subsequent recruitment of death-domain-containing IRAK1 and IRAK4 to the receptor complex [2] where IRAK1 is phosphorylated and activated by IRAK4 [5][6][7]. This is followed by intensive autophosphorylation of IRAK1 [5,6], its interaction with TRAF6 and subsequent dissociation of IRAK1 and TRAF6 as binding partners from the receptor complex [8][9][10]. TRAF6 then interacts with TIFA (TRAF-interacting protein with a FHA domain), which promotes oligomerization and ubiquitylation (Box 1) of the former [11].…”

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

“…Myd88 then associates with members of the IL-1R-associated kinase (IRAK) family (IRAK-1-4) [1]. IRAK-1 is recruited to Myd88 within a complex with another protein termed Tollinteracting protein (Tollip) [3]. The IRAK-Myd88 association triggers hyperphosphorylation of IRAK-1 by itself and other kinases, such as IRAK-4 [4,5], which leads to its dissociation from Myd88 and Tollip and its interaction with the downstream adaptor tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF-6) [3].…”

“…IRAK-1 is recruited to Myd88 within a complex with another protein termed Tollinteracting protein (Tollip) [3]. The IRAK-Myd88 association triggers hyperphosphorylation of IRAK-1 by itself and other kinases, such as IRAK-4 [4,5], which leads to its dissociation from Myd88 and Tollip and its interaction with the downstream adaptor tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF-6) [3]. TRAF-6 is an ubiquitin ligase [6,7] and activates transforming growth factor-b (TGF-b)-activating kinase (TAK1) [8], which in turn promotes downstream activation of the IkB kinases (IKK), IKKa and IKKb.…”