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

    13 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

    Fingerprint

    Interleukin-1 Receptors
    Toll-Like Receptors
    Interleukins
    Phosphotransferases
    Cell Survival
    Chemical activation
    Cells
    Interleukin-1
    Amplification
    Interleukin-1 Type I Receptors
    Mutagenesis
    Protein Conformation
    Caspase 3
    Alanine
    Conformations
    Proteins
    Genes
    Scanning
    Mutation

    Cite this

    Zhang, Xiao ; Montagut Pino, Gemma ; Shephard, Freya ; Kiss-Toth, Endre ; Qwarnstrom, Eva E. / Distinct control of MyD88 adapter-dependent and Akt kinase-regulated responses by the interleukin (IL)-1RI co-receptor, TILRR. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 15. pp. 12348-12352.
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    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.",
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    Distinct control of MyD88 adapter-dependent and Akt kinase-regulated responses by the interleukin (IL)-1RI co-receptor, TILRR. / Zhang, Xiao; Montagut Pino, Gemma; Shephard, Freya; Kiss-Toth, Endre; Qwarnstrom, Eva E.

    In: Journal of Biological Chemistry, Vol. 287, No. 15, 06.04.2012, p. 12348-12352.

    Research output: Contribution to journalArticle

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    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.

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    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.

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