TLR5- cluster of differentiation 285

By: Stephen Jones
Submitted: 2008-07-02 16:12:48
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Toll-like receptor 5 (TLR5), a member of the evolutionarily conserved Toll-like receptor family, has evolved to permit mammals specifically to detect flagellated bacterial pathogens. Like all other members of the TLR family, TLR5 is composed of an extracellular domain containingmultiple leucine-rich repeats (LRRs), a transmembrane region,and a cytoplasmic tail containing the conserved TIR domain.The TLR5 gene has been mapped to chromosome 1q41-42. The gene encodes a putative 858 aminio acid protein with a calculated molecular weight of 91 kDa. It is most closely related to TLR3 with 26% overall amino acid sequence identity.

In vivo,TLR5 mRNA is expressed as a single transcript in ovary, prostate. In vitro, TLR5 is most significantly upregulated in PMA-differentiated THP-1 cells by autocrine IL-6, IL-10, and TNF-α, but is also elevated by IFN-γβ. Further, TLR5 mRNA expression is elevated after exposure to both Gram-positive and Gram-negative bacteria. Ex vivo,however, granulocyte and in particular monocyte TLR5 expression is downregulated upon exposure to Gram-negative bacteria (1, 2).

TLR5 is expressed in epithelialcells of the airways, intestine, and urogenital tract, as wellas on hemopoietic cells of the innate and adaptive immune systemand has recently been shown to be involved in the transportof flagellated Salmonella typhimurium from the intestinal tractto the mesenteric lymph nodes. Like other described TLRs, TLR5 utilizes the adaptor proteinMyD88 and IL-1 receptor-associated kinase (IRAK) to activatea signal transduction cascade that results in the activationof the transcription factor NF-B necessary for flagellin-inducedeffects on gene expression (4). TLR5 forms a homodimer as well as a heterodimer with TLR4. Both complexes function to recognize the Flagellin protein of both Gram-positive and Gram-negative bacteria, and activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production. TheTLR5 recognition site on flagellin isconserved among a wide variety of flagellated bacteriaalthough select bacterial species possess unique flagellin moleculesthat evade TLR5 recognition. These amino acids are locatedin the highly conserved D1 domain of the flagellin protein andcluster on the convex surface that contacts adjacent flagellinmonomers in the flagellar protofilament. Mutating individualresidues in the TLR5 recognition site significantly reducedor completely abolished bacterial motility, suggesting thatevolving a functional flagellin that evades TLR5 would requirea complex series of mutations (5).

 Reference:

1. Zarember, K.A. & P.J. Godowski (2002) J. Immunol. 168:554.

2. Muzio, M. et al. (2000) J. Immunol. 164:5998.

3. Yimin Yu Am J Physiol Gastrointest Liver Physiol 285: G282-G290, 2003

4. Nature. 2001 Apr 26;410(6832):1099-103.

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