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Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production

Nature Immunology volume 10, pages 1089–1095 (2009)Cite this article

Abstract

Toll-like receptors (TLRs) are pivotal in innate immunity and inflammation. Here we show that genetic deficiency in Peli1, an E3 ubiquitin ligase, attenuated the induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and rendered mice resistant to septic shock. Peli1 was required for TLR3-induced activation of IκB kinase (IKK) and its 'downstream' target, transcription factor NF-κB, but was dispensable for IKK–NF-κB activation induced by several other TLRs and the interleukin 1 (IL-1) receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.

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Figure 1: Peli1−/− mice are resistant to LPS- and poly(I:C)-induced death.
Figure 2: Peli1 is required for TLR3- and TLR4-mediated induction of proinflammatory genes.
Figure 3: Peli1 regulates B cell activation and survival.
Figure 4: Peli1 is essential for the activation of IKK–NF-κB by TLR3.
Figure 5: Dispensable role of Peli1 in IL-1R signaling.
Figure 6: Peli1 interacts with and ubiquitinates RIP1.

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Acknowledgements

We thank the Texas Institute for Genomic Medicine for Peli1-knockout mice; R. Beyaert (Ghent University) for E-tag-fused Peli1 and mutants; J. Hiscott (McGill University) for GST-IRF3 (amino acids 380–427); V. Chau (Pennsylvania State University College of Medicine) for anti-ubiquitin; and M.K. Offermann and W.J. Kaiser (Emory University) for CMV14-3xFlag-TRIF, pCMV10-3XFlag-RIP1 and pcDNA3-myc-RIP1. Supported by the US National Institutes of Health (AI057555, AI064639 and GM84459).

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  1. Mikyoung Chang and Wei Jin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Mikyoung Chang, Wei Jin & Shao-Cong Sun

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  1. Mikyoung Chang
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M.C. and W.J. designed and did the research and prepared the figures; S.-C.S. designed the research and wrote the manuscript.

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Correspondence to Shao-Cong Sun.

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Chang, M., Jin, W. & Sun, SC. Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nat Immunol 10, 1089–1095 (2009). https://doi.org/10.1038/ni.1777

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