Abstract
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.
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Abbreviations
- DD:
-
death domain
- EDA:
-
ectodysplasin-A
- EDAR:
-
ectodysplasin-A receptor
- IBD:
-
inflammatory bowel disease
- IκB:
-
inhibitor of kappa B
- IKKβ:
-
IκB kinase beta
- IL-1R:
-
interleukin (IL)-1 receptor
- IRAK:
-
IL-1R-associated kinase
- JNK:
-
c-Jun N-terminal kinase
- MyD88:
-
myeloid differentiation primary response gene 88
- NF-κB:
-
nuclear factor kappa B
- Nup98:
-
nuclear pore complex protein 98
- PIDD:
-
p53-induced protein with a DD
- PLA2G4C:
-
phospholipase A2 group IVC
- TIR:
-
Toll–IL-1R domain
- TLR:
-
Toll-like receptor
- TM:
-
transmembrane
- TNFα:
-
tumor necrosis factor alpha
- TNFAIP3:
-
TNF alpha-induced protein 3
- TNF-RI:
-
tumor necrosis factor receptor type I
- TNFRSF9:
-
TNF receptor superfamily member 9
- TRAF6:
-
TNF receptor-associated factor 6
- Unc5CL:
-
Unc5C-like protein
- UPA, domain found in Unc5:
-
PIDD and Ankyrins
- ZU5:
-
domain found in ZO-1 and Unc5
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Acknowledgements
We thank C Thomas for critically reading the manuscript and A Tardivel, S Hertig, G Guarda and TK Vogt for their technical help. This work was supported by grants from the Swiss National Science Foundation, NCCR Molecular Oncology, the EU-FP6 framework program RTN-ApopTrain, the Institute for Arthritis Research and Fondation Louis-Jeantet.
Author Contributions
LXH and JT designed research; LXH, MR, DCR, FS, KS, MQ, OG and PS performed the experiments; LXH, KS and OG analyzed the data; LXH and JT wrote the paper.
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Heinz, L., Rebsamen, M., Rossi, D. et al. The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade. Cell Death Differ 19, 722–731 (2012). https://doi.org/10.1038/cdd.2011.147
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DOI: https://doi.org/10.1038/cdd.2011.147
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