Structural Basis of the IL-1 Receptor TIR Domain-mediated IL-1 Signaling

Overview

Journal iScience

Publisher Cell Press

Date 2022 Jun 27

PMID 35754719

Authors

Jianjie Zhou

Yu Xiao

Yifei Ren

Jiwan Ge

Xinquan Wang

Affiliations

Soon will be listed here.

Abstract

The cytoplasmic Toll/interleukin-1 receptor (TIR) domains of IL-1 receptors (IL-1Rs) are evolutionally conserved and essential for transmitting signals. IL-1RAcP is a shared co-receptor in the IL-1R family for signaling. Its splicing form IL-1RAcPb contains a different TIR domain and is unable to transduce NF-κB signaling. Here, we determined crystal structures of TIR domains of IL-1RAcPb and other IL-1Rs including IL-18Rβ, IL-1RAPL2, and zebrafish SIGIRR (zSIGIRR). Structurally variant regions in the TIR domain important for signaling were revealed by structural comparisons. Taking advantage of the IL-1RAcP/IL-1RAcPb pair, we demonstrated that differential TIR domain determines signaling discrepancies between IL-1RAcP and IL-1RAcPb. We also proved the functional importance of two helices (αC and αD) in the structurally variable regions and pinpointed critical residues in αC and αD for signaling. These results collectively provide additional and important knowledge for fully understanding the molecular basis of IL-1R TIR domain in mediating signaling.

Citing Articles

IL-18 biology in severe asthma.

Thawanaphong S, Nair A, Volfson E, Nair P, Mukherjee M Front Med (Lausanne). 2024; 11:1486780.

PMID: 39554494 PMC: 11566457. DOI: 10.3389/fmed.2024.1486780.

Structural characterization of TIR-domain signalosomes through a combination of structural biology approaches.

Bhatt A, Mishra B, Gu W, Sorbello M, Xu H, Ve T IUCrJ. 2024; 11(Pt 5):695-707.

PMID: 39190506 PMC: 11364022. DOI: 10.1107/S2052252524007693.

References

Ma S, Lapin D, Liu L, Sun Y, Song W, Zhang X . Direct pathogen-induced assembly of an NLR immune receptor complex to form a holoenzyme. Science. 2020; 370(6521). DOI: 10.1126/science.abe3069. View

Radons J, Dove S, Neumann D, Altmann R, Botzki A, Martin M . The interleukin 1 (IL-1) receptor accessory protein Toll/IL-1 receptor domain: analysis of putative interaction sites in vitro mutagenesis and molecular modeling. J Biol Chem. 2003; 278(49):49145-53. DOI: 10.1074/jbc.M306077200. View

Toshchakov V, Szmacinski H, Couture L, Lakowicz J, Vogel S . Targeting TLR4 signaling by TLR4 Toll/IL-1 receptor domain-derived decoy peptides: identification of the TLR4 Toll/IL-1 receptor domain dimerization interface. J Immunol. 2011; 186(8):4819-27. PMC: 3071460. DOI: 10.4049/jimmunol.1002424. View

Essuman K, Summers D, Sasaki Y, Mao X, DiAntonio A, Milbrandt J . The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017; 93(6):1334-1343.e5. PMC: 6284238. DOI: 10.1016/j.neuron.2017.02.022. View

Prieto G, Snigdha S, Baglietto-Vargas D, Smith E, Berchtold N, Tong L . Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus. Proc Natl Acad Sci U S A. 2015; 112(36):E5078-87. PMC: 4568670. DOI: 10.1073/pnas.1514486112. View

Kaplan-Turkoz B, Koelblen T, Felix C, Candusso M, OCallaghan D, Vergunst A . Structure of the Toll/interleukin 1 receptor (TIR) domain of the immunosuppressive Brucella effector BtpA/Btp1/TcpB. FEBS Lett. 2013; 587(21):3412-6. DOI: 10.1016/j.febslet.2013.09.007. View

Jang T, Park H . Crystal structure of TIR domain of TLR6 reveals novel dimeric interface of TIR-TIR interaction for toll-like receptor signaling pathway. J Mol Biol. 2014; 426(19):3305-3313. DOI: 10.1016/j.jmb.2014.07.024. View

Lin Z, Lu J, Zhou W, Shen Y . Structural insights into TIR domain specificity of the bridging adaptor Mal in TLR4 signaling. PLoS One. 2012; 7(4):e34202. PMC: 3317499. DOI: 10.1371/journal.pone.0034202. View

Bovijn C, Desmet A, Uyttendaele I, Van Acker T, Tavernier J, Peelman F . Identification of binding sites for myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 in MyD88 adapter-like (Mal). J Biol Chem. 2013; 288(17):12054-66. PMC: 3636891. DOI: 10.1074/jbc.M112.415810. View

10.

Guven-Maiorov E, Keskin O, Gursoy A, VanWaes C, Chen Z, Tsai C . The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway. Sci Rep. 2015; 5:13128. PMC: 4544004. DOI: 10.1038/srep13128. View

11.

Ve T, Williams S, Kobe B . Structure and function of Toll/interleukin-1 receptor/resistance protein (TIR) domains. Apoptosis. 2014; 20(2):250-61. DOI: 10.1007/s10495-014-1064-2. View

12.

Wang D, Zhang S, Li L, Liu X, Mei K, Wang X . Structural insights into the assembly and activation of IL-1β with its receptors. Nat Immunol. 2010; 11(10):905-11. DOI: 10.1038/ni.1925. View

13.

Valkov E, Stamp A, DiMaio F, Baker D, Verstak B, Roversi P . Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection. Proc Natl Acad Sci U S A. 2011; 108(36):14879-84. PMC: 3169156. DOI: 10.1073/pnas.1104780108. View

14.

Yabuuchi K, Minami M, Katsumata S, Satoh M . Localization of type I interleukin-1 receptor mRNA in the rat brain. Brain Res Mol Brain Res. 1994; 27(1):27-36. DOI: 10.1016/0169-328x(94)90180-5. View

15.

Garlanda C, Dinarello C, Mantovani A . The interleukin-1 family: back to the future. Immunity. 2013; 39(6):1003-18. PMC: 3933951. DOI: 10.1016/j.immuni.2013.11.010. View

16.

Smith D, Lipsky B, Russell C, Ketchem R, Kirchner J, Hensley K . A central nervous system-restricted isoform of the interleukin-1 receptor accessory protein modulates neuronal responses to interleukin-1. Immunity. 2009; 30(6):817-31. PMC: 4103746. DOI: 10.1016/j.immuni.2009.03.020. View

17.

Nimma S, Gu W, Maruta N, Li Y, Pan M, Saikot F . Structural Evolution of TIR-Domain Signalosomes. Front Immunol. 2021; 12:784484. PMC: 8635717. DOI: 10.3389/fimmu.2021.784484. View

18.

Gay N, Keith F . Drosophila Toll and IL-1 receptor. Nature. 1991; 351(6325):355-6. DOI: 10.1038/351355b0. View

19.

Horsefield S, Burdett H, Zhang X, Manik M, Shi Y, Chen J . NAD cleavage activity by animal and plant TIR domains in cell death pathways. Science. 2019; 365(6455):793-799. DOI: 10.1126/science.aax1911. View

20.

Nguyen L, Rothwell N, Pinteaux E, Boutin H . Contribution of interleukin-1 receptor accessory protein B to interleukin-1 actions in neuronal cells. Neurosignals. 2011; 19(4):222-30. DOI: 10.1159/000330803. View