Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 15, Pages 12348-12352Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.C111.321711
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Funding
- Biotechnology and Biological Sciences Research Council [BB/C515798/1, BBS/B/04056]
- British Heart Foundation [PG/2000094, PG/07/094/23742]
- Biotechnology and Biological Sciences Research Council [BB/C515798/1, BB/J009687/1, BBS/B/04056] Funding Source: researchfish
- BBSRC [BB/J009687/1] Funding Source: UKRI
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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-kappa 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 alpha-helical structure of the TILRR core protein. The results indicate a role for TILRR in selective amplification of NF-kappa B responses through IL-1RI and suggest that the specificity is determined by changes in receptor conformation and adapter protein recruitment.
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