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, Daniela V. Pilonetto, Ricardo Pasquini, Grover C. Bagby

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5290-5298
Number of pages9
JournalBlood
Volume114
Issue number26
DOIs
StatePublished - Dec 17 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'TLR8-dependent TNF-α overexpression in Fanconi anemia group C cells'. Together they form a unique fingerprint.

  • Cite this

    Vanderwerf, S. M., Svahn, J., Olson, S., Rathbun, R. K., Harrington, C., Yates, J., Keeble, W., Anderson, D. C., Anur, P., Pereira, N. F., Pilonetto, D. V., Pasquini, R., & Bagby, G. C. (2009). TLR8-dependent TNF-α overexpression in Fanconi anemia group C cells. Blood, 114(26), 5290-5298. https://doi.org/10.1182/blood-2009-05-222414