The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade
| Autor: | Heinz LX Rebsamen M Rossi DC Staehli F Schroder K Quadroni M Gross O Schneider P Tschopp J |
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| Zdroj: | Cell Death Differ |
| Popis: | The family of death domain (DD) containing proteins are involved in many cellular processes including apoptosis inflammation and development. One of these molecules the adapter protein MyD88 is a key factor in innate and adaptive immunity that integrates signals from the Toll like receptor/interleukin (IL) 1 receptor (TLR/IL 1R) superfamily by providing an activation platform for IL 1R associated kinases (IRAKs). Here we show that the DD containing protein Unc5CL (also known as ZUD) is involved in a novel MyD88 independent mode of IRAK signaling that culminates in the activation of the transcription factor nuclear factor kappa B (NF kappaB) and c Jun N terminal kinase. Unc5CL required IRAK1 IRAK4 and TNF receptor associated factor 6 but not MyD88 for its ability to activate these pathways. Interestingly the protein is constitutively autoproteolytically processed and is anchored by its N terminus specifically to the apical face of mucosal epithelial cells. Transcriptional profiling identified mainly chemokines including IL 8 CXCL1 and CCL20 as Unc5CL target genes. Its prominent expression in mucosal tissues as well as its ability to induce a pro inflammatory program in cells suggests that Unc5CL is a factor in epithelial inflammation and immunity as well as a candidate gene involved in mucosal diseases such as inflammatory bowel disease |
| Databáze: | OpenAIRE |
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