Alternate transcription of the Toll-like receptor signaling cascade

Christine A Wells, Alistair M Chalk, Alistair Forrest, Darrin Taylor, Nic Waddell, Kate Schroder, Stewart R Himes, Geoffrey J Faulkner, Yu-Lan-Sandra Lo, Takeya Kasukawa, Hideya Kawaji, Chikatoshi Kai, Jun Kawai, Shintaro Katayama, Piero Carninci, Yoshihide Hayashizaki, David A Hume, Sean M Grimmond

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62 Citations (Scopus)

Abstract

BACKGROUND: Alternate splicing of key signaling molecules in the Toll-like receptor (Tlr) cascade has been shown to dramatically alter the signaling capacity of inflammatory cells, but it is not known how common this mechanism is. We provide transcriptional evidence of widespread alternate splicing in the Toll-like receptor signaling pathway, derived from a systematic analysis of the FANTOM3 mouse data set. Functional annotation of variant proteins was assessed in light of inflammatory signaling in mouse primary macrophages, and the expression of each variant transcript was assessed by splicing arrays. RESULTS: A total of 256 variant transcripts were identified, including novel variants of Tlr4, Ticam1, Tollip, Rac1, Irak1, 2 and 4, Mapk14/p38, Atf2 and Stat1. The expression of variant transcripts was assessed using custom-designed splicing arrays. We functionally tested the expression of Tlr4 transcripts under a range of cytokine conditions via northern and quantitative real-time polymerase chain reaction. The effects of variant Mapk14/p38 protein expression on macrophage survival were demonstrated. CONCLUSION: Members of the Toll-like receptor signaling pathway are highly alternatively spliced, producing a large number of novel proteins with the potential to functionally alter inflammatory outcomes. These variants are expressed in primary mouse macrophages in response to inflammatory mediators such as interferon-gamma and lipopolysaccharide. Our data suggest a surprisingly common role for variant proteins in diversification/repression of inflammatory signaling.
Original languageEnglish
Pages (from-to)1 - 17
Number of pages17
JournalGenome Biology
Volume7
Issue number2 (R10)
Publication statusPublished - 2006

Cite this

Wells, C. A., Chalk, A. M., Forrest, A., Taylor, D., Waddell, N., Schroder, K., Himes, S. R., Faulkner, G. J., Lo, Y-L-S., Kasukawa, T., Kawaji, H., Kai, C., Kawai, J., Katayama, S., Carninci, P., Hayashizaki, Y., Hume, D. A., & Grimmond, S. M. (2006). Alternate transcription of the Toll-like receptor signaling cascade. Genome Biology, 7(2 (R10)), 1 - 17.