TY - JOUR
T1 - Distinct control of MyD88 adapter-dependent and Akt kinase-regulated responses by the interleukin (IL)-1RI co-receptor, TILRR
AU - Zhang, Xiao
AU - Montagut Pino, Gemma
AU - Shephard, Freya
AU - Kiss-Toth, Endre
AU - Qwarnstrom, Eva E.
N1 - MEDLINE® is the source for the MeSH terms of this document.
PY - 2012/4/6
Y1 - 2012/4/6
N2 - Inflammatory responses are controlled through members of the interleukin-1 receptor (IL-1R)/Toll-like receptor superfamily. Our earlier work demonstrates that the IL-1 receptor type 1 (IL-1RI) co-receptor, Toll-like and IL-1 receptor regulator (TILRR), amplifies IL-1 activation of NF-?B and inflammatory genes. Here we show that TILRR similarly promotes IL-1-induced anti-apoptotic signals and reduces caspase-3 activity. Further, the TILRR-induced effects on cell survival and inflammatory responses are controlled through distinct parts of the IL-1RI regulatory Toll IL-1 receptor (TIR) domain. Alanine-scanning mutagenesis identified a functional TILRR mutant (R425A), which blocked increases in cell survival and upstream activation of Akt but had no effect on amplification of MyD88- dependent inflammatory responses. A second mutant (D448A) blocked TILRR potentiation of MyD88-dependent signals and inflammatory activation but had no impact on cell survival. Secondary structure predictions suggested that the mutations induce distinct alterations in the a-helical structure of the TILRR core protein. The results indicate a role for TILRR in selective amplification of NF-?B responses through IL-1RI and suggest that the specificity is determined by changes in receptor conformation and adapter protein recruitment.
AB - Inflammatory responses are controlled through members of the interleukin-1 receptor (IL-1R)/Toll-like receptor superfamily. Our earlier work demonstrates that the IL-1 receptor type 1 (IL-1RI) co-receptor, Toll-like and IL-1 receptor regulator (TILRR), amplifies IL-1 activation of NF-?B and inflammatory genes. Here we show that TILRR similarly promotes IL-1-induced anti-apoptotic signals and reduces caspase-3 activity. Further, the TILRR-induced effects on cell survival and inflammatory responses are controlled through distinct parts of the IL-1RI regulatory Toll IL-1 receptor (TIR) domain. Alanine-scanning mutagenesis identified a functional TILRR mutant (R425A), which blocked increases in cell survival and upstream activation of Akt but had no effect on amplification of MyD88- dependent inflammatory responses. A second mutant (D448A) blocked TILRR potentiation of MyD88-dependent signals and inflammatory activation but had no impact on cell survival. Secondary structure predictions suggested that the mutations induce distinct alterations in the a-helical structure of the TILRR core protein. The results indicate a role for TILRR in selective amplification of NF-?B responses through IL-1RI and suggest that the specificity is determined by changes in receptor conformation and adapter protein recruitment.
UR - http://www.scopus.com/inward/record.url?scp=84859495961&partnerID=8YFLogxK
U2 - 10.1074/jbc.C111.321711
DO - 10.1074/jbc.C111.321711
M3 - Article
AN - SCOPUS:84859495961
SN - 0021-9258
VL - 287
SP - 12348
EP - 12352
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 15
ER -