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 language | English |
|---|---|
| Pages (from-to) | 5290-5298 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 114 |
| Issue number | 26 |
| DOIs | |
| Publication status | Published - Dec 17 2009 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
TLR8-dependent TNF-α overexpression in Fanconi anemia group C cells. / Vanderwerf, Scott M.; Svahn, Johanna; Olson, Susan; Rathbun, R. Keaney; Harrington, Christina; Yates, Jane; Keeble, Winifred; Anderson, David C.; Anur, Praveen; Pereira, Noemi F.; Pilonetto, Daniela V.; Pasquini, Ricardo; Bagby, Grover C.
In: Blood, Vol. 114, No. 26, 17.12.2009, p. 5290-5298.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - TLR8-dependent TNF-α overexpression in Fanconi anemia group C cells
AU - Vanderwerf, Scott M.
AU - Svahn, Johanna
AU - Olson, Susan
AU - Rathbun, R. Keaney
AU - Harrington, Christina
AU - Yates, Jane
AU - Keeble, Winifred
AU - Anderson, David C.
AU - Anur, Praveen
AU - Pereira, Noemi F.
AU - Pilonetto, Daniela V.
AU - Pasquini, Ricardo
AU - Bagby, Grover C.
PY - 2009/12/17
Y1 - 2009/12/17
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2009-05-222414
DO - 10.1182/blood-2009-05-222414
M3 - Article
VL - 114
SP - 5290
EP - 5298
JO - Blood
JF - Blood
SN - 0006-4971
IS - 26
ER -