FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4

Kuppusamy Balamurugan, Shikha Sharan, Kimberly D. Klarmann, Youhong Zhang, Vincenzo Coppola, Glenn H. Summers, Thierry Roger, Deborah K. Morrison, Jonathan R. Keller and Esta Sterneck ()
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Kuppusamy Balamurugan: Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA
Shikha Sharan: Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA
Kimberly D. Klarmann: Basic Science Program, SAIC-Frederick, Inc., Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, PO Box B, Frederick, Maryland 21702-1201, USA
Youhong Zhang: Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA
Vincenzo Coppola: Wexner Medical Center, Ohio State University-Comprehensive Cancer Center, Ohio State University-CCC, 988 Biological Research Tower 460 West 12th Avenue
Glenn H. Summers: Laboratory Animal Sciences Program, SAIC-Frederick, NCI, FNLCR
Thierry Roger: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne
Deborah K. Morrison: Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA
Jonathan R. Keller: Basic Science Program, SAIC-Frederick, Inc., Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, PO Box B, Frederick, Maryland 21702-1201, USA
Esta Sterneck: Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract Toll-like receptor 4 (Tlr4) has a pivotal role in innate immune responses, and the transcription factor CCAAT/enhancer binding protein delta (C/EBPδ, Cebpd) is a Tlr4-induced gene. Here we identify a positive feedback loop in which C/EBPδ activates Tlr4 gene expression in macrophages and tumour cells. In addition, we discovered a negative feedback loop whereby the tumour suppressor FBXW7α (FBW7, Cdc4), whose gene expression is inhibited by C/EBPδ, targets C/EBPδ for degradation when C/EBPδ is phosphorylated by GSK-3β. Consequently, FBXW7α suppresses Tlr4 expression and responses to the ligand lipopolysaccharide. FBXW7α depletion alone is sufficient to augment pro-inflammatory signalling in vivo. Moreover, as inflammatory pathways are known to modulate tumour biology, Cebpd null mammary tumours, which have reduced metastatic potential, show altered expression of inflammation-associated genes. Together, these findings reveal a role for C/EBPδ upstream of Tlr4 signalling and uncover a function for FBXW7α as an attenuator of inflammatory signalling.

Date: 2013
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DOI: 10.1038/ncomms2677

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