title: The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade.
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.
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland. leonhard.heinz@gmail.com
authors.forename: L X
authors.initials: LX
authors.lastname: Heinz
authors.forename: M
authors.initials: M
authors.lastname: Rebsamen
authors.forename: D C
authors.initials: DC
authors.lastname: Rossi
authors.forename: F
authors.initials: F
authors.lastname: Staehli
authors.forename: K
authors.initials: K
authors.lastname: Schroder
authors.forename: M
authors.initials: M
authors.lastname: Quadroni
authors.forename: O
authors.initials: O
authors.lastname: Gross
authors.forename: P
authors.initials: P
authors.lastname: Schneider
authors.forename: J
authors.initials: J
authors.lastname: Tschopp
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D018925:Chemokines; D047908:Intracellular Signaling Peptides and Proteins; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C486467:UNC5CL protein, human; C486466:Unc5cl protein, mouse; D017346:Protein Serine-Threonine Kinases