Pathology Research

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TLR8-dependent TNF-α overexpression in Fanconi anemia group C cells

Scott M. Vanderwerf; Johanna Svahn; Susan Olson; R. Keaney Rathbun; Christina Harrington; Jane Yates; Winifred Keeble; David C. Anderson; Praveen Anur; Noemi F. Pereira; et al. (Profiled Authors: Grover Bagby; Christina (Chris) Harrington; Susan Olson)

Blood. 2009;114(26):5290-5298.

Tumor necrosis factor alpha (TNF-α) production is abnormally high in Fanconi anemia (FA) cells and contributes to the hematopoietic defects seen in FAcomplementation 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-α production in mutant cells depended upon TLR8 and the canonical downstream signaling intermediates interleukin 1 receptor-associated kinase (IRAK) and IκB kinase-alpha/beta. FANCC-deficient THP-1 cells and macrophages from Fancc ^-/- mice overexpressed TNF-α 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-α overproduction. In conclusion, FANCC suppresses TNF-α 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. © 2009 by The American Society of Hematology.

PMID: 19850743     PMCID: PMC2796134

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