The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade

Cell Death Differ. 2012 Apr;19(4):722-31. doi: 10.1038/cdd.2011.147. Epub 2011 Dec 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Chemokines / biosynthesis
  • Chemokines / genetics
  • Gene Expression Regulation / physiology
  • HEK293 Cells
  • Humans
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / physiology*

Substances

  • Carrier Proteins
  • Chemokines
  • Intracellular Signaling Peptides and Proteins
  • MYD88 protein, human
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • UNC5CL protein, human
  • Unc5cl protein, mouse
  • Protein-Serine-Threonine Kinases