IRAK3 inhibits TLR-dependent NF-kappaB activation in salmonid fish. IRAK3 in salmonid fish

Engaged Toll-like receptors recruit via their TIR domains the principal adaptor protein MYD88 and IL1R-associated kinases (IRAKs) into a post-receptor signalling complex. This is known as Myddosome and represents an excellent platform to transmit the pathogen signal into the cytoplasm. IRAK3 (alias IRAK-M) drives out IRAK1 from the Myddosome complex and instead forms the ‘IRAK-M Myddosome’ with MYD88 and IRAK4. In doing so, IRAK3 mediates a delayed NF-kB activity phase inducing the expression of further inhibitory genes such as INPP5D , TNFAIP3, SOCS or NFKBIA. As these factors all together limit TLR-mediated signalling, IRAK3 has an indirect, but diversified effect. Transcriptome profiling studies of the innate immune response to bacterial infections in zebrafish and rainbow trout revealed large sets of infection markers including irak3. In this study, we cloned multiple irak3 isoforms from rainbow trout and expressed the most abundant irak3 variant in a model cell system. Irak3 overexpression elevated the basal level of NF-kB and blunted, after pathogen stimulation, the TLR-dependent activation of NF-kB.