TLR8-dependent TNF-(alpha) overexpression in Fanconi anemia group C cells.
Tumor necrosis factor alpha (TNF-alpha) production is abnormally high in Fanconi anemia (FA) cells and contributes to the hematopoietic defects seen in FA complementation group C-deficient (Fancc(-/-)) mice. Applying gene expression microarray and proteomic methods to studies on FANCC-deficient cells we found that genes encoding proteins directly involved in ubiquitinylation ... are overrepresented in the signature of FA bone marrow cells and that ubiquitinylation profiles of FA-C and complemented cells were substantially different. Finding that Toll-like receptor 8 (TLR8) was one of the proteins ubiquitinylated only in mutant cells, we confirmed that TLR8 (or a TLR8-associated protein) is ubiquitinylated in mutant FA-C cells and that TNF-alpha production in mutant cells depended upon TLR8 and the canonical downstream signaling intermediates interleukin 1 receptor-associated kinase (IRAK) and IkappaB kinase-alpha/beta. FANCC-deficient THP-1 cells and macrophages from Fancc(-/-) mice overexpressed TNF-alpha in response to TLR8 agonists but not other TLR agonists. Ectopically expressed FANCC point mutants were capable of fully complementing the mitomycin-C hypersensitivity phenotype of FA-C cells but did not suppress TNF-alpha overproduction. In conclusion, FANCC suppresses TNF-alpha production in mononuclear phagocytes by suppressing TLR8 activity and this particular function of FANCC is independent of its function in protecting the genome from cross-linking agents.
Mesh Terms:
Animals, Blotting, Western, Electrophoretic Mobility Shift Assay, Fanconi Anemia, Fanconi Anemia Complementation Group C Protein, Gene Expression, Gene Expression Profiling, Humans, Immunoprecipitation, Leukocytes, Mononuclear, Mice, Mice, Knockout, Oligonucleotide Array Sequence Analysis, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Toll-Like Receptor 8, Tumor Necrosis Factor-alpha, Ubiquitination, Up-Regulation
Animals, Blotting, Western, Electrophoretic Mobility Shift Assay, Fanconi Anemia, Fanconi Anemia Complementation Group C Protein, Gene Expression, Gene Expression Profiling, Humans, Immunoprecipitation, Leukocytes, Mononuclear, Mice, Mice, Knockout, Oligonucleotide Array Sequence Analysis, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Toll-Like Receptor 8, Tumor Necrosis Factor-alpha, Ubiquitination, Up-Regulation
Blood
Date: Dec. 17, 2009
PubMed ID: 19850743
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