Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Bypassing PELO-mediated ATPase activation of the NLR is a common pathogenic cause of NLR-associated autoinflammatory diseases

Cellular & Molecular Immunology (2024)Cite this article

Subjects

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are evolutionarily conserved intracellular pattern recognition receptors (PRRs) that sense microbial and danger signals, trigger immediate host defenses, and prime the adaptive immune response for long-lasting protection [1]. In humans, 22 known NLRs exist, and mutations in NLR family genes are associated with a wide range of inflammatory and autoimmune conditions, including hereditary periodic fever syndromes, Crohn’s disease, Blau’s syndrome, infantile enterocolitis, multiple sclerosis, and asthma [2, 3]. Collectively, these disorders can be categorized as NLR-associated autoinflammatory diseases.

The hallmark feature of NLRs is their central NOD (or NACHT) domain—an ATPase domain—while the N-terminal and C-terminal domains exhibit variability. Most NLRs have a C-terminal leucine-rich repeat (LRR). The N-terminal varies among NLRs and is responsible for homotypic protein-protein interactions [4]. The C-terminal LRR functions as an inhibitory domain in NLRs, and the NACHT domain hydrolyzes ATP upon activation. After ligand binding, the C-terminal LRR domain of most NLRs undergoes a conformational change, exposing the N-terminal domain. This conformational shift allows for the formation of oligomeric scaffolds, which subsequently interact with downstream signaling adaptors or effectors. Notably, ATPase activity within NLRs is essential for complex formation [4]. Despite the diversity of inflammatory pathways activated by different NLR family members, recent research has revealed a common checkpoint of ATPase activation that could govern the activation of all NLRs [5].

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Chen G, Shaw MH, Kim YG, Nunez G. NOD-like receptors: role in innate immunity and inflammatory disease. Annu Rev Pathol. 2009;4:365–98. https://doi.org/10.1146/annurev.pathol.4.110807.092239

    Article  CAS  PubMed  Google Scholar 

  2. Geddes K, Magalhaes JG, Girardin SE. Unleashing the therapeutic potential of NOD-like receptors. Nat Rev Drug Discov. 2009;8:465–79. https://doi.org/10.1038/nrd2783

    Article  CAS  PubMed  Google Scholar 

  3. Zhong Y, Kinio A, Saleh M. Functions of NOD-like receptors in human diseases. Front Immunol. 2013;4:333. https://doi.org/10.3389/fimmu.2013.00333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Meunier E, Broz P. Evolutionary convergence and divergence in NLR function and structure. Trends Immunol. 2017;38:744–57. https://doi.org/10.1016/j.it.2017.04.005

    Article  CAS  PubMed  Google Scholar 

  5. Wu X, Yang ZH, Wu J, Han J. Ribosome-rescuer PELO catalyzes the oligomeric assembly of NOD-like receptor family proteins via activating their ATPase enzymatic activity. Immunity. 2023;56:926–43.e927. https://doi.org/10.1016/j.immuni.2023.02.014.

    Article  CAS  PubMed  Google Scholar 

  6. Doma MK, Parker R. Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature. 2006;440:561–4. https://doi.org/10.1038/nature04530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shoemaker CJ, Eyler DE, Green R. Dom34:Hbs1 promotes subunit dissociation and peptidyl-tRNA drop-off to initiate no-go decay. Science. 2010;330:369–72. https://doi.org/10.1126/science.1192430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pisareva VP, Skabkin MA, Hellen CU, Pestova TV, Pisarev AV. Dissociation by Pelota, Hbs1 and ABCE1 of mammalian vacant 80S ribosomes and stalled elongation complexes. EMBO J. 2011;30:1804–17. https://doi.org/10.1038/emboj.2011.93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsuboi T, Kuroha K, Kudo K, Makino S, Inoue E, Kashima I, et al. Dom34:hbs1 plays a general role in quality-control systems by dissociation of a stalled ribosome at the 3’ end of aberrant mRNA. Mol Cell. 2012;46:518–29. https://doi.org/10.1016/j.molcel.2012.03.013

    Article  CAS  PubMed  Google Scholar 

  10. Guydosh NR, Green R. Dom34 rescues ribosomes in 3’ untranslated regions. Cell. 2014;156:950–62. https://doi.org/10.1016/j.cell.2014.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16:407–20. https://doi.org/10.1038/nri.2016.58

    Article  CAS  PubMed  Google Scholar 

  12. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87. https://doi.org/10.1038/nm.3893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Louvrier C, Assrawi E, El Khouri E, Melki I, Copin B, Bourrat E, et al. NLRP3-associated autoinflammatory diseases: Phenotypic and molecular characteristics of germline versus somatic mutations. J Allergy Clin Immunol. 2020;145:1254–61. https://doi.org/10.1016/j.jaci.2019.11.035

    Article  CAS  PubMed  Google Scholar 

  14. Hochheiser IV, Behrmann H, Hagelueken G, Rodríguez-Alcázar JF, Kopp A, Latz E, et al. Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation. Sci Adv. 2022;8:eabn7583. https://doi.org/10.1126/sciadv.abn7583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Samson JM, Ravindran Menon D, Vaddi PK, Kalani Williams N, Domenico J, Zhai Z, et al. Computational modeling of NLRP3 identifies enhanced ATP binding and multimerization in Cryopyrin-associated periodic syndromes. Front Immunol. 2020;11:584364. https://doi.org/10.3389/fimmu.2020.584364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Lu Zhou for help with proofreading the manuscript. This work was supported by the National Natural Science Foundation of China (82388201 to JH, 32170751 to Z-HY), the Fundamental Research Funds for the Central Universities (226-2024-00015 to XW), the National Key R&D Program of China (2020YFA0803500 to JH), the CAMS Innovation Fund for Medical Science (2019-I2M-5-062 to JH), Fujian Province Central to Local Science and Technology Development Special Program (No. 2022L3079 to JH) and the Fu-Xia-Quan Zi-Chuang District Cooperation Program (No. 3502ZCQXT2022003 to JH).

Author information

Author notes

  1. These authors contributed equally: Xiurong Wu, Zhang-Hua Yang.

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China

    Xiurong Wu, Yue Zheng, Jianfeng Wu & Jiahuai Han

  2. Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310012, China

    Xiurong Wu

  3. Research Unit of Cellular Stress of CAMS, Xiang’an Hospital of Xiamen University, Cancer Research Center of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China

    Zhang-Hua Yang & Jiahuai Han

  4. Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310012, China

    Zhang-Hua Yang

  5. Laboratory Animal Center, Xiamen University, Xiamen, Fujian, 361102, China

    Jianfeng Wu & Jiahuai Han

Authors
  1. Xiurong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhang-Hua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yue Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jianfeng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiahuai Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XW and Z-HY performed most of the experiments; YZ and JW participated in the experiments; and XW, Z-HY, and JH analyzed the data and wrote the manuscript. XW and JH conceived the project and supervised the study.

Corresponding authors

Correspondence to Xiurong Wu or Jiahuai Han.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, X., Yang, ZH., Zheng, Y. et al. Bypassing PELO-mediated ATPase activation of the NLR is a common pathogenic cause of NLR-associated autoinflammatory diseases. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01162-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41423-024-01162-w

Search

Advanced search

Quick links