TILRR, a novel IL-1RI co-receptor, potentiates MyD88 recruitment to control Ras-dependent amplification of NF-kappaB.

J Biol Chem 2010 Mar 25;285(10):7222-32. Epub 2009 Nov 25.

Units of Cell Biology, University of Sheffield, Sheffield S102RX, United Kingdom.

Host defense against infection is induced by Toll-like and interleukin (IL)-1 receptors, and controlled by the transcription factor NF-kappaB. Our earlier studies have shown that IL-1 activation impacts cytoskeletal structure and that IL-1 receptor (IL-1RI) function is substrate-dependent. Here we identify a novel regulatory component, TILRR, which amplifies activation of IL-1RI and coordinates IL-1-induced control with mechanotransduction. We show that TILRR is a highly conserved and widely expressed enhancer of IL-1-regulated inflammatory responses and, further, that it is a membrane-bound glycosylated protein with sequence homology to members of the FRAS-1 family. We demonstrate that TILRR is recruited to the IL-1 receptor complex and magnifies signal amplification by increasing receptor expression and ligand binding. In addition, we show that the consequent potentiation of NF-kappaB is controlled through IL-1RI-associated signaling components in coordination with activation of the Ras GTPase. Using mutagenesis, we demonstrate that TILRR function is dependent on association with its signaling partner and, further, that formation of the TILRR-containing IL-1RI complex imparts enhanced association of the MyD88 adapter during ligand-induced activation of NF-kappaB. We conclude that TILRR is an IL-1RI co-receptor, which associates with the signaling receptor complex to enhance recruitment of MyD88 and control Ras-dependent amplification of NF-kappaB and inflammatory responses.

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M109.073429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844171PMC
March 2010
22 Reads

Publication Analysis

Top Keywords

il-1ri co-receptor
8
ras-dependent amplification
8
control ras-dependent
8
amplification nf-kappab
8
receptor complex
8
demonstrate tilrr
8
il-1 receptor
8
inflammatory responses
8
tilrr
6
nf-kappab
5
il-1ri
5
magnifies signal
4
consequent potentiation
4
complex magnifies
4
potentiation nf-kappab
4
nf-kappab controlled
4
recruited il-1
4
addition consequent
4
tilrr recruited
4
ligand binding
4

References

(Supplied by CrossRef)

Similar Publications