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.

  • Research Highlight
  • Published:

K63-linked polyubiquitination of IRF1: an essential step in the IL-1 signaling cascade

Cellular & Molecular Immunology volume 11, pages 407–409 (2014)Cite this article

Interleukin 1 (IL-1) is a pleiotropic cytokine that regulates immune and inflammatory responses by inducing the expression of a variety of pro-inflammatory cytokines and chemokines. IL-1 exerts its pro-inflammatory effects primarily by activating nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs).1 After binding to its receptor complex, IL-1R, IL-1 recruits the cytosolic adaptor MyD88 via the Toll–IL-1R domain of IL-1R.2 MyD88 subsequently recruits the IRAK4 and IRAK1 kinases, resulting in the hyperphosphorylation of IRAK1 by IRAK4.3 This leads to binding and activation of the E3 ubiquitin ligase TRAF6, which contains a ubiquitination-mediating RING ligase domain.4 TRAF6 conjugates K63-linked polyubiquitin chains both to itself and to IRAK1, promoting recruitment of the TAK1 kinase, the TAK1-binding proteins TAB2 and TAB3, and the linear ubiquitin assembly complex. Linear ubiquitin assembly complex subsequently generates linear polyubiquitin chains that recruit the kinase IKK (‘inhibitor of NF-κB kinase’) complex.5 Subsequently, TRAF6 mediates the attachment to IKKγ (a regulatory subunit of the IKK complex) and TAK1 of K63-linked polyubiquitin chains, which leads to the activation of NF-κB and MAPKs.6,7,8

IRF1, IRF3, IRF5 and IRF7 mediate critical Toll-like receptor- and cell-specific regulation of type I interferons.9,10 While IL-1 is known to induce expression of IRF1, the roles of IRF1 in IL-1-mediated immune and inflammatory responses, and the mechanisms by which it is activated, remain unknown.

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

Relevant articles

Open Access articles citing this article.

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

Figure 1

References

  1. Arend WP . The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev 2002; 13: 323–340.

    Article  CAS  PubMed  Google Scholar 

  2. Janssens S, Beyaert R . A universal role for MyD88 in TLR/IL-1R-mediated signaling. Trends Biochem Sci 2002; 27: 474–482.

    Article  CAS  PubMed  Google Scholar 

  3. Kim TW, Staschke K, Bulek K, Yao J, Peters K, Oh KH et al. A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. J Exp Med 2007; 204: 1025–1036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Inoue J, Gohda J, Akiyama T . Characteristics and biological functions of TRAF6. Adv Exp Med Biol 2007; 597: 72–79.

    Article  PubMed  Google Scholar 

  5. Emmerich CH, Ordureau A, Strickson S, Arthur JS, Pedrioli PG, Komander D et al. Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc Natl Acad Sci USA 2013; 110: 15247–15252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen ZJ . Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 2005; 7: 758–765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Deng L, Wang C, Spencer E, Yang L, Braun A, You J et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 2000; 103: 351–361.

    Article  CAS  PubMed  Google Scholar 

  8. Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD . Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and Toll-like receptor-mediated NF-kappaB activation. Mol Cell Biol 2008; 28: 3538–3547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hoshino K, Sasaki I, Sugiyama T, Yano T, Yamazaki C, Yasui T et al. Critical role of IkappaB Kinase alpha in TLR7/9-induced type I IFN production by conventional dendritic cells. J Immunol 2010; 184: 3341–3345.

    Article  CAS  PubMed  Google Scholar 

  10. Balkhi MY, Fitzgerald KA, Pitha PM . Functional regulation of MyD88-activated interferon regulatory factor 5 by K63-linked polyubiquitination. Mol Cell Biol 2008; 28: 7296–7308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Harikumar KB, Yester JW, Surace MJ, Oyeniran C, Price MM, Huang WC et al. K63-linked polyubiquitination of transcription factor IRF1 is essential for IL-1-induced production of chemokines CXCL10 and CCL5. Nat Immunol 2014; 15: 231–238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM, Kim EY et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 2010; 465: 1084–1088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Paugh SW, Paugh BS, Rahmani M, Kapitonov D, Almenara JA, Kordula T et al. A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood 2008; 112: 1382–1391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J et al. Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 2007; 12: 445–456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tada Y, Ho A, Matsuyama T, Mak TW . Reduced incidence and severity of antigen-induced autoimmune diseases in mice lacking interferon regulatory factor-1. J Exp Med 1997; 185: 231–238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Dr JL Wang, Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China. E-mail: jlwang@zju.edu.cn

Authors and Affiliations

  1. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China

    Jianli Wang

  2. Clinical Medical College of Shandong University, Jinan, China

    Tianxiao Wang

Authors
  1. Tianxiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianli Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, T., Wang, J. K63-linked polyubiquitination of IRF1: an essential step in the IL-1 signaling cascade. Cell Mol Immunol 11, 407–409 (2014). https://doi.org/10.1038/cmi.2014.35

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2014.35

This article is cited by

Search

Advanced search

Quick links