Immunology

Sorting Out Toll in Flies

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Science  13 Apr 2012:
Vol. 336, Issue 6078, pp. 133
DOI: 10.1126/science.336.6078.133-a

Seminal studies of the Toll pathway in Drosophila led to the discovery of Toll-like receptors (TLRs) in mammals and paved the way toward our current understanding of innate immune signaling. In mammals, pairs of adapter proteins couple to TLRs to activate downstream signaling. In particular, a “sorting” adapter (either TIRAP or TRAM) helps to localize TLRs to a region of the cell that promotes signaling. Once sorted, a “signaling” adapter (either MyD88 or TRIF) then binds and initiates downstream signaling that culminates in changes in gene expression. Surprisingly, however, homologs for the sorting adapters have not been found in flies, and the MyD88 homolog in flies (dMyD88) does not appear to act as a signaling adapter. Marek and Kagan investigated the innate signaling mechanisms in Drosophila and found that dMyD88 instead functions as a sorting adapter and recruits Tube, which functions as a signaling adapter. Similar to mammalian cells, the sorting ability of dMyD88 was dependent on a C-terminal phosphoinositide-binding domain. Flies that expressed dMyD88 lacking this domain exhibited impaired immune defense, and other insect species expressed phosphoinositide-binding dMyD88 homologs, demonstrating the important role of this signaling module in immune defense.

Immunity 36, 10.1016/j.immuni.2012.01.019 (2012).

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