TLR8-dependent TNF-(alpha) overexpression in Fanconi anemia group C cells

Blood. 2009 Dec 17;114(26):5290-8. doi: 10.1182/blood-2009-05-222414. Epub 2009 Oct 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Electrophoretic Mobility Shift Assay
  • Fanconi Anemia / genetics
  • Fanconi Anemia / metabolism*
  • Fanconi Anemia Complementation Group C Protein / deficiency
  • Fanconi Anemia Complementation Group C Protein / genetics
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Immunoprecipitation
  • Leukocytes, Mononuclear / metabolism
  • Mice
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Toll-Like Receptor 8 / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Ubiquitination / physiology
  • Up-Regulation


  • Fanconi Anemia Complementation Group C Protein
  • RNA, Small Interfering
  • Toll-Like Receptor 8
  • Tumor Necrosis Factor-alpha