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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

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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.

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  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

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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

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