Distinct control of MyD88 adapter-dependent and Akt kinase-regulated responses by the interleukin (IL)-1RI co-receptor, TILRR

Xiao Zhang, Gemma Montagut Pino, Freya Shephard, Endre Kiss-Toth, Eva E. Qwarnstrom

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)12348-12352
    Number of pages5
    JournalJournal of Biological Chemistry
    Volume287
    Issue number15
    DOIs
    Publication statusPublished - 6 Apr 2012

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