Tribbles 2 (Trib2) is a novel regulator of toll-like receptor 5 signaling

Shu Chen Wei, Ian M. Rosenberg, Zhifang Cao, Alan S. Huett, Ramnik J. Xavier, Daniel K. Podolsky

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: Toll-like receptors (TLRs) are expressed by a variety of cells, including intestinal epithelia. However, the full spectrum of regulators modulating innate responses via TLRs has not been delineated. Tribbles (Trib) have been identified as a highly conserved family of kinase-like proteins. We sought to clarify the role of Trib2 in the TLR signaling pathway. Methods: Trib2 mRNA and protein levels were analyzed by quantitative polymerase chain reaction (PCR) and western blot, respectively. Immunohistochemical staining was used to determine the expression of Trib2 in human tissue. Involvement of Trib2 in nuclear factor kappa B (NF-κB) pathways was assessed in epithelial cells by NF-κB reporter assay. Proteins that interacted with Trib2 were identified by mass spectrometry and confirmed by immunoprecipitation. The domain essential for Trib2 function was mapped using truncated constructs. Results: Trib2 expression is decreased in active inflamed tissue from patients with inflammatory bowel disease (IBD). Trib2 is expressed in human and mouse colonic epithelium as well as immune cells, and its expression in epithelium is inducible in a ligand-dependent manner by TLR5 ligand stimulation. Trib2 inhibits TLR5-mediated activation of NF-κB downstream of TRAF6. Trib2 selectively modulates mitogen-activated protein kinase (MAPK) pathways p38 and Jun N-terminal kinase (JNK) but not p44/p42 (ERK1/2). NF-jB2 (p100) was identified as a Trib2 binding partner in regulating the TLR5 signaling pathway that leads to inhibition of NF-κB activity. Residues 158-177 in the Trib2 kinase-like domain are required for Trib2 function. Conclusions: These observations indicate that Trib2 is a novel regulator in the TLR5 signaling pathway and altered expression of Trib2 may play a role in IBD.

Original languageEnglish (US)
Pages (from-to)877-888
Number of pages12
JournalInflammatory Bowel Diseases
Volume18
Issue number5
DOIs
StatePublished - May 2012

Fingerprint

Toll-Like Receptor 5
NF-kappa B
Toll-Like Receptors
Inflammatory Bowel Diseases
Phosphotransferases
Epithelium
TNF Receptor-Associated Factor 6
Ligands
Toll-Like Receptor 2
p38 Mitogen-Activated Protein Kinases
Intestinal Mucosa
Immunoprecipitation
Protein Kinases
Mass Spectrometry
Proteins
Western Blotting
Epithelial Cells
Staining and Labeling
Polymerase Chain Reaction
Messenger RNA

Keywords

  • IBD
  • MAPK
  • NF-κB2
  • Nuclear factor kappa b
  • Toll-like receptor
  • Tribbles 2

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

Tribbles 2 (Trib2) is a novel regulator of toll-like receptor 5 signaling. / Wei, Shu Chen; Rosenberg, Ian M.; Cao, Zhifang; Huett, Alan S.; Xavier, Ramnik J.; Podolsky, Daniel K.

In: Inflammatory Bowel Diseases, Vol. 18, No. 5, 05.2012, p. 877-888.

Research output: Contribution to journalArticle

Wei, Shu Chen ; Rosenberg, Ian M. ; Cao, Zhifang ; Huett, Alan S. ; Xavier, Ramnik J. ; Podolsky, Daniel K. / Tribbles 2 (Trib2) is a novel regulator of toll-like receptor 5 signaling. In: Inflammatory Bowel Diseases. 2012 ; Vol. 18, No. 5. pp. 877-888.
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AU - Rosenberg, Ian M.

AU - Cao, Zhifang

AU - Huett, Alan S.

AU - Xavier, Ramnik J.

AU - Podolsky, Daniel K.

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