MyD88: An Adapter That Recruits IRAK to the IL-1 Receptor Complex

Abstract

IL-1 is a proinflammatory cytokine that signals through a receptor complex of two different transmembrane chains to generate multiple cellular responses, including activation of the transcription factor NF-kappaB. Here we show that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. MyD88 binds to both IRAK (IL-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of IRAK with the receptor. Ectopic expression of MyD88 or its death domain-containing N-terminus activates NF-kappaB. The C-terminus of MyD88 interacts with the IL-1 receptor and blocks NF-kappaB activation induced by IL-1, but not by TNF. Thus, MyD88 plays the same role in IL-1 signaling as TRADD and Tube do in TNF and Toll pathways, respectively: it couples a serine/threonine protein kinase to the receptor complex.

MyD genes in negative growth control

“…Whether it functions like TRADD is not known negative which blocks NF-kB activation by IL-1, but not by TNF. Both the N-and C-terminal fragments of MyD88 were observed to interact with IRAK (Wesche et al, 1997a). Formation of MyD88 homodimers, mediated via the death domain, was observed as well.…”

“…Several reports in the last year have identi®ed MyD88 as an adapter that recruits IRAK to the IL-1 receptor complex Wesche et al, 1997a;Muzio et al, 1997) (Figure 3). It was shown that following IL-1 stimulation MyD88 binds to both IRAK and the IL-1R/IL-1AcP receptor complex, thereby linking IRAK to the receptor.…”

Effects of repeated handling and air exposure on the immune response and the disease resistance of gibel carp (Carassius auratus gibelio) over winter

“…All TLRs except TLR3 and TLR4 have been shown to require MyD88 for effective downstream signaling, dividing the TLR family between MyD88-dependent and MyD88-independent members [15]. In the case of pathogenic invading, MyD88 was up-regulated to enhance the activation of downstream transcription factors, such as NF-kB and AP-1 [16]. In the MyD88-independent TLR signaling pathway, TLR3 induce the activation of the IFN-b promoter, a function unimpaired by the knockdown of MyD88 [17].…”

Expression and function analysis of two naturally truncated MyD88 variants in the Pacific oyster Crassostrea gigas

“…Unexpectedly, we found two novel truncated forms of Myd88 lacking DD domain, CgMyD88-T1 and CgMyD88-T2. Both CgMyD88Ts contain the conserved TIR domain, which has previously been proved to be required for mediating TLR/MyD88 heterodimerization to activate the followed signaling transduction [19].…”