title: Distinct control of MyD88 adapter-dependent and Akt kinase-regulated responses by the interleukin (IL)-1RI co-receptor, TILRR.
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-κB 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 α-helical structure of the TILRR core protein. The results indicate a role for TILRR in selective amplification of NF-κB responses through IL-1RI and suggest that the specificity is determined by changes in receptor conformation and adapter protein recruitment.
authors.affiliation: Cell Biology Group, University of Sheffield, Sheffield S10 2RX, United Kingdom.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.forename: Gemma Montagut
authors.initials: GM
authors.lastname: Pino
authors.forename: Freya
authors.initials: F
authors.lastname: Shephard
authors.forename: Endre
authors.initials: E
authors.lastname: Kiss-Toth
authors.forename: Eva E
authors.initials: EE
authors.lastname: Qwarnstrom
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D006367:HeLa Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C548979:Frem1 protein, human; C508590:IL1R1 protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D018123:Receptors, Interleukin; D053573:Receptors, Interleukin-1 Type I; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3