Skip to main content
SpringerLink
Log in

TIR enzymatic functions: signaling molecules and receptor mechanisms

  • Review
  • Published:
aBIOTECH Aims and scope Submit manuscript

Abstract

The evolutionarily conserved Toll/Interleukin-1 Receptor (TIR) domains across kingdoms of prokaryotes, plants, and animals play critical roles in innate immunity. Recent studies have revealed the enzymatic functions of TIRs, the structural bases of TIRs as holoenzymes, and the identity of TIR-generated small signaling molecules and their receptors, which significantly advanced our understanding on TIR-mediated immune signaling pathways. We reviewed the most up-to-date findings in TIR enzymatic functions from the perspectives of signaling molecules and receptor mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

References

  • Bayless AM, Chen S, Ogden SC, Xu X, Sidda JD, Manik MK, Li S, Kobe B, Ve T, Song L et al (2023) Plant and prokaryotic TIR domains generate distinct cyclic ADPR NADase products. Sci Adv 9:eade8487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bi GZ, Su M, Li N, Liang Y, Dang S, Xu JC, Hu MJ, Wang JZ, Zou MX, Deng YA et al (2021) The ZAR1 resistosome is a calcium-permeable channel triggering plant immune signaling. Cell 184:3528

    Article  CAS  PubMed  Google Scholar 

  • DiAntonio A, Milbrandt J, Figley MD (2021) The SARM1 TIR NADase: mechanistic similarities to bacterial phage defense and toxin-antitoxin systems. Front Immunol 12:752898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eastman S, Bayless A, Guo M (2022a) The Nucleotide revolution: immunity at the intersection of Toll/Interleukin-1 receptor domains, nucleotides, and Ca2+. Mol Plant Microbe 35:964–976

    Article  CAS  Google Scholar 

  • Eastman S, Smith T, Zaydman MA, Kim P, Martinez S, Damaraju N, DiAntonio A, Milbrandt J, Clemente TE, Alfano JR et al (2022b) A phytobacterial TIR domain effector manipulates NAD(+) to promote virulence. New Phytol 233:890–904

    Article  CAS  PubMed  Google Scholar 

  • Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J (2017) The SARM1 Toll/Interleukin-1 receptor domain possesses intrinsic NAD(+) cleavage activity that promotes pathological axonal degeneration. Neuron 93(1334–1343):e1335

    Google Scholar 

  • Essuman K, Summers DW, Sasaki Y, Mao X, Yim AKY, DiAntonio A, Milbrandt J (2018) TIR domain proteins are an ancient family of NAD(+)-consuming enzymes. Curr Biol 28(421–430):e424

    Google Scholar 

  • Essuman K, Milbrandt J, Dangl JL, Nishimura MT (2022) Shared TIR enzymatic functions regulate cell death and immunity across the tree of life. Science 377:eabo0001

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald KA, Kagan JC (2020) Toll-like receptors and the control of immunity. Cell 180:1044–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forderer A, Li E, Lawson AW, Deng YN, Sun Y, Logemann E, Zhang X, Wen J, Han Z, Chang J et al (2022) A wheat resistosome defines common principles of immune receptor channels. Nature 610:532–539

    Article  PubMed  PubMed Central  Google Scholar 

  • Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J (2015) SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 348:453–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horsefield S, Burdett H, Zhang X, Manik MK, Shi Y, Chen J, Qi T, Gilley J, Lai JS, Rank MX et al (2019) NAD(+) cleavage activity by animal and plant TIR domains in cell death pathways. Science 365:793–799

    Article  CAS  PubMed  Google Scholar 

  • Huang S, Jia A, Song W, Hessler G, Meng Y, Sun Y, Xu L, Laessle H, Jirschitzka J, Ma S et al (2022) Identification and receptor mechanism of TIR-catalyzed small molecules in plant immunity. Science 377:eabq3297

    Article  CAS  PubMed  Google Scholar 

  • Jacob P, Kim NH, Wu FH, El Kasmr F, Chi Y, Walton WG, Furzer OJ, Lietzan AD, Sunil S, Kempthorn K et al (2021) Plant “helper” immune receptors are Ca2+-permeable nonselective cation channels. Science 373:420–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jia A, Huang S, Song W, Wang J, Meng Y, Sun Y, Xu L, Laessle H, Jirschitzka J, Hou J et al (2022) TIR-catalyzed ADP-ribosylation reactions produce signaling molecules for plant immunity. Science 377:eabq8180

    Article  CAS  PubMed  Google Scholar 

  • Jubic LM, Saile S, Furzer OJ, El Kasmi F, Dangl JL (2019) Help wanted: helper NLRs and plant immune responses. Curr Opin Plant Biol 50:82–94

    Article  CAS  PubMed  Google Scholar 

  • Ka D, Oh H, Park E, Kim JH, Bae E (2020) Structural and functional evidence of bacterial antiphage protection by Thoeris defense system via NAD(+) degradation. Nat Commun 11:1–8

    Article  Google Scholar 

  • Ko KW, Devault L, Sasaki Y, Milbrandt J, DiAntonio A (2021) Live imaging reveals the cellular events downstream of SARM1 activation. eLife 10:1–21

    Article  Google Scholar 

  • Koopal B, Potocnik A, Mutte SK, Aparicio-Maldonado C, Lindhoud S, Vervoort JJM, Brouns SJJ, Swarts DC (2022) Short prokaryotic Argonaute systems trigger cell death upon detection of invading DNA. Cell 185:1471–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lapin D, Kovacova V, Sun X, Dongus JA, Bhandari D, von Born P, Bautor J, Guarneri N, Rzemieniewski J, Stuttmann J et al (2019) A coevolved EDS1-SAG101-NRG1 module mediates cell death signaling by TIR-domain immune receptors. Plant Cell 31:2430–2455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leavitt A, Yirmiya E, Amitai G, Lu A, Garb J, Herbst E, Morehouse BR, Hobbs SJ, Antine SP, Sun ZYJ et al (2022) Viruses inhibit TIR gcADPR signalling to overcome bacterial defence. Nature 611:326–331

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Pazyra-Murphy MF, Avizonis D, de RussoTavaresSa M, Tang S, Chen CY, Hsueh YP, Bergholz JS, Jiang T, Zhao JJ et al (2022) Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN. J Cell Biol 221:1–19

    Article  Google Scholar 

  • Liu XX, Wan L (2022) Molecular insights into the biochemical functions and signalling mechanisms of plant NLRs. Mol Plant Pathol 23:772–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma S, Lapin D, Liu L, Sun Y, Song W, Zhang X, Logemann E, Yu D, Wang J, Jirschitzka J et al (2020) Direct pathogen-induced assembly of an NLR immune receptor complex to form a holoenzyme. Science 370:1–10

    Article  Google Scholar 

  • Manik MK, Shi Y, Li SL, Zaydman MA, Damaraju N, Eastman S, Smith TG, Gu WX, Masic V, Mosaiab T et al (2022) Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling. Science 377:1–11

    Article  Google Scholar 

  • Martin R, Qi T, Zhang H, Liu F, King M, Toth C, Nogales E, Staskawicz BJ (2020) Structure of the activated ROQ1 resistosome directly recognizing the pathogen effector XopQ. Science 370:1–7

    Article  Google Scholar 

  • Medzhitov R, PrestonHurlburt P, Janeway CA (1997) A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature 388:394–397

    Article  CAS  PubMed  Google Scholar 

  • Michelle T, Hulin LH, Jones JDG, Ma W (2023) Pangenomic analysis reveals plant NAD manipulation as an important virulence activity of bacterial pathogen effectors. P Natl Acad Sci USA 120(7):e2217114120

    Article  Google Scholar 

  • Morehouse BR, Govande AA, Millman A, Keszei AFA, Lowey B, Ofir G, Shao SC, Sorek R, Kranzusch PJ (2020) STING cyclic dinucleotide sensing originated in bacteria. Nature 586:429–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ofir G, Herbst E, Baroz M, Cohen D, Millman A, Doron S, Tal N, Malheiro DBA, Malitsky S, Amitai G et al (2021) Antiviral activity of bacterial TIR domains via immune signalling molecules. Nature 600:116–120

    Article  CAS  PubMed  Google Scholar 

  • Ronald PC, Beutler B (2010) Plant and animal sensors of conserved microbial signatures. Science 330:1061–1064

    Article  CAS  PubMed  Google Scholar 

  • Sun XH, Lapin D, Feehan JM, Stolze SC, Kramer K, Dongus JA, Rzemieniewski J, Blanvillain-Baufume S, Harzen A, Bautor J et al (2021) Pathogen effector recognition-dependent association of NRG1 with EDS1 and SAG101 in TNL receptor immunity. Nat Commun 12:1–15

    Google Scholar 

  • Tian L, Lu JX, Li X (2022) Differential requirement of TIR enzymatic activities in TIR-type immune receptor SNC1-mediated immunity. Plant Physiol 190:2094–2098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner S, Stuttmann J, Rietz S, Guerois R, Brunstein E, Bautor J, Niefind K, Parker JE (2013) Structural basis for signaling by exclusive EDS1 heteromeric complexes with SAG101 or PAD4 in plant innate immunity. Cell Host Microbe 14:619–630

    Article  CAS  PubMed  Google Scholar 

  • Wan L, Essuman K, Anderson RG, Sasaki Y, Monteiro F, Chung EH, Osborne Nishimura E, DiAntonio A, Milbrandt J, Dangl JL et al (2019) TIR domains of plant immune receptors are NAD(+)-cleaving enzymes that promote cell death. Science 365:799–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Hu M, Wang J, Qi J, Han Z, Wang G, Qi Y, Wang HW, Zhou JM, Chai J (2019) Reconstitution and structure of a plant NLR resistosome conferring immunity. Science 364:1–11

    Article  Google Scholar 

  • Wein T, Sorek R (2022) Bacterial origins of human cell-autonomous innate immune mechanisms. Nat Rev Immunol 22:629–638

    Article  CAS  PubMed  Google Scholar 

  • Whitham S, Dinesh-Kumar SP, Choi D, Hehl R, Corr C, Baker B (1994) The product of the tobacco mosaic virus resistance gene N: similarity to toll and the interleukin-1 receptor. Cell 78:1101–1115

    Article  CAS  PubMed  Google Scholar 

  • Yu DL, Song W, Tan EYJ, Liu L, Cao Y, Jirschitzka J, Li ER, Logemann E, Xu CR, Huang SJ et al (2022) TIR domains of plant immune receptors are 2′,3′-cAMP/cGMP synthetases mediating cell death. Cell 185:2370–2386

    Article  CAS  PubMed  Google Scholar 

  • Zhao YB, Liu MX, Chen TT, Ma X, Li ZK, Zheng Z, Zheng SR, Chen L, Li YZ, Tang LR et al (2022) Pathogen effector AvrSr35 triggers Sr35 resistosome assembly via a direct recognition mechanism. Sci Adv 8:eabq5108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou JM, Zhang Y (2020) Plant immunity: danger perception and signaling. Cell 181:978–989

    Article  CAS  PubMed  Google Scholar 

  • Zhu S, Jeong RD, Venugopal SC, Lapchyk L, Navarre D, Kachroo A, Kachroo P (2011) SAG101 forms a ternary complex with EDS1 and PAD4 and is required for resistance signaling against turnip crinkle virus. PLoS Pathog 7:e1002318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

L.W. was supported by Chinese Academy of Sciences Strategic Priority Research Program (Type-B; Project number: XDB27040214).

Author information

Authors and Affiliations

  1. National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, 200032, China

    Li Wan

Authors
  1. Li Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Wan.

Ethics declarations

Conflict of interest

The author declares no competing interests.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wan, L. TIR enzymatic functions: signaling molecules and receptor mechanisms. aBIOTECH 4, 172–175 (2023). https://doi.org/10.1007/s42994-023-00104-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42994-023-00104-w

Keywords

Search

Navigation