Trends in Biochemical Sciences
ReviewA universal role for MyD88 in TLR/IL-1R-mediated signaling
Section snippets
Genomic organization and expression of MyD88
Until now, MyD88 orthologs have been described in human, mouse, rat, Xenopus and Drosophila. No orthologs have yet been found in Caenorhabditis elegans, although the identification of a C. elegans toll homolog suggests the existence of a toll-induced pathway in this organism [13]. Phylogenetic analysis of the TIR family of proteins reveals that MyD88 is most closely related to SIGIRR (for single Ig IL-1R related molecule), an orphan receptor with one extracellular immunoglobulin repeat [14].
The
Role of MyD88 in TLR/IL-1R-mediated responses
Although the extracellular domains of the TLRs and IL-1Rs are divergent, their intracellular domains share a high degree of similarity, and activate similar signaling cascades upon stimulation. One of the best-known signaling pathways that is induced upon activation of TLR or IL-1R, is the nuclear factor κB (NF-κB) pathway. Members of the NF-κB family of transcription factors form dimers (e.g. p50/p65) that regulate the expression of a variety of cellular genes that are involved in the control
MyD88-mediated activation of NF-κB and MAPKs
Wesche et al. [10] provided the first biochemical evidence that a 35-kDa protein, later identified as MyD88, could be coimmunoprecipitated in an IL-1-dependent manner with IL-1R and IRAK. Although earlier reports assumed that MyD88 mediated the recruitment of IRAK to the IL-1R, a recent report has clearly demonstrated that IRAK can also be recruited in a MyD88-independent manner, probably through interaction with the adapter protein Tollip [32]. Nowadays, it is generally accepted that MyD88 is
Mal/TIRAP mediates MyD88-independent signaling
The observation that TLR3- and TLR4-induced responses are only partially affected in MyD88-deficient cells had already suggested that they could signal through a different adapter protein. Recently, a novel MyD88-like adapter protein (Mal), independently identified as a novel TIR-domain-containing adapter protein (TIRAP), was shown to mediate TLR4-, but not IL-1R- or TLR9-, dependent signaling 44., 45.. The N terminus of Mal/TIRAP shows no similarity to any known protein motifs, and the C
MyD88 and tube in insect innate immunity
The Drosophila toll pathway, which is involved in dorso–ventral axis polarization during development and also mediates the insect immune response to fungi and gram-positive bacteria, is similar to the mammalian TLR/IL1-R pathway (reviewed in [52]) (Fig. 4). Activation of toll initiates a signaling cascade that culminates in the activation of a transcription factor of the Rel family (dorsal in the developmental response and dif in the innate immune response). This requires the activity of an
Antagonists of MyD88 signaling
Viruses try to escape host-defense reactions by exploiting various strategies. Searches for new TIR-domain-containing proteins led to the identification of two Vaccinia virus open-reading frames, A46R and A52R, which encode only a TIR domain [58]. Upon overexpression in HEK293T cells, A46R and A52R inhibited IL-1R- and TLR4-dependent signaling, presumably by docking to the receptor and preventing MyD88 binding. In this way, they mimic the dominant-negative effect of a truncated MyD88 protein
A role for MyD88 in apoptosis?
In most cells, activation of TLR/IL-1R family members does not result in apoptosis, but rather triggers expression of cell survival genes and inflammatory genes, thereby enabling the cell to defend the body against invading pathogens. Only at later time points, when the infection does not seem to be resolved, does it make sense to induce programmed cell death. Reports on IL-1R- or TLR-induced apoptosis are scarce and such induction is often cell-type specific or dependent on the simultaneous
A role for MyD88 in development?
As already mentioned, MyD88-deficient mice did not show any defects in development. By contrast, evidence for a role of MyD88 in Xenopus development has been proposed, based on microinjection of Xenopus embryos with mRNA encoding a truncated Xenopus MyD88 protein that lacks the DD. This abolished the induction of several regulatory genes in the Spemann organizer region (a region in the blastopore that is the source of signals coordinating the movements of gastrulation and the pattern of tissue
Future perspectives
Numerous reports from the past few years established MyD88 as a universal and essential adapter for the TLR/IL-1R family, initiating downstream signaling to MAPKs and NF-κB-mediated gene expression. However, it seems contradictory that, throughout evolution, different receptors evolved with different ligand specificities, only to then converge on the activation of one single adapter protein. An important issue for the future will be to elucidate how specificity is obtained. Part of the answer
Acknowledgements
S.J. is a research associate with the FWO-Vlaanderen. Research was supported by grants from the FWO-Vlaanderen and the IAP. We thank W. Drijvers, P. De Bleser and M. Vandecasteele for their help with the preparation of the figures and the manuscript. We apologize for those papers that have not been cited because of space restrictions.
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