The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade
| Autor: | Kate Schroder, Manuele Rebsamen, Leonhard X. Heinz, J. Tschopp, Pascal Schneider, Olaf Gross, Manfredo Quadroni, Francesco Staehli, D C Rossi |
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| Rok vydání: | 2011 |
| Předmět: |
Protein Serine-Threonine Kinases
Biology Mice 03 medical and health sciences 0302 clinical medicine Animals Humans Molecular Biology Transcription factor 030304 developmental biology Death domain Original Paper 0303 health sciences Intracellular Signaling Peptides and Proteins NF-kappa B Cell Biology Inflammatory Bowel Diseases IRAK4 NFKB1 Cell biology CCL20 HEK293 Cells Gene Expression Regulation 030220 oncology & carcinogenesis Myeloid Differentiation Factor 88 Cancer research Tumor necrosis factor alpha Chemokines Signal transduction Carrier Proteins Signal Transduction |
| Zdroj: | CELL DEATH AND DIFFERENTIATION |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/cdd.2011.147 |
| 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-κB) 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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