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F-box protein FBXL19–mediated ubiquitination and degradation of the receptor for IL-33 limits pulmonary inflammation

Nature Immunology volume 13, pages 651–658 (2012)Cite this article

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Abstract

The ST2L receptor for interleukin 33 (IL-33) mediates pulmonary inflammation and immune system–related disorders, such as asthma and rheumatoid arthritis. At present, very little is known about the molecular regulation of ST2L expression. Here we found that FBXL19, an 'orphan' member of the Skp1–Cullin–F-box family of E3 ubiquitin ligases, selectively bound to ST2L to mediate its polyubiquitination and elimination in the proteasome. Degradation of ST2L involved phosphorylation of ST2L at Ser442 catalyzed by the kinase GSK3β. Overexpression of FBXL19 abrogated the proapoptotic and inflammatory effects of IL-33 and lessened the severity of lung injury in mouse models of pneumonia. Our results suggest that modulation of the IL-33–ST2L axis by ubiquitin ligases might serve as a unique strategy for lessening pulmonary inflammation.

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Figure 1: FBXL19 mediates the degradation of ST2L via the ubiquitin-proteasome system.
Figure 2: IL-33 mediates the degradation of ST2L.
Figure 3: FBXL19 mediates the IL-33-induced degradation of ST2L via the ubiquitin-proteasome system.
Figure 4: GSK3β phosphorylates and promotes the degradation of ST2L.
Figure 5: Identification of a GSK3β-phosphorylation site in ST2L.
Figure 6: Identification of an ST2L ubiquitin-acceptor site and FBXL19-docking site.
Figure 7: FBXL19 attenuates IL-33-induced degradation of cortactin and apoptosis.
Figure 8: FBXL19 diminishes endotoxin-induced acute lung injury.

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Acknowledgements

We thank L. Wallace for technical assistance. This study is based on work supported in part by the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. Supported by the US Department of Veterans Affairs (Merit Review Award), the US National Institutes of Health (R01 HL01916 to Y.Z. and R01 HL096376, R01 HL097376 and R01 HL098174 to R.K.M.) and the American Heart Association (12SDG9050005 to J.Z.). The contents presented do not represent the views of the Department of Veterans Affairs or the United States Government.

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Author notes

  1. Rama K Mallampalli and Yutong Zhao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine and the Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Jing Zhao, Jianxin Wei, Rachel K Mialki, Daniel F Mallampalli, Bill B Chen, Tiffany Coon, Chunbin Zou, Rama K Mallampalli & Yutong Zhao

  2. Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Rama K Mallampalli

  3. Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA

    Rama K Mallampalli

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Contributions

J.Z. and Y.Z. designed the study, did experiments, analyzed the data and wrote the manuscript; J.W., R.K.Mi. and D.F.M. did experiments; B.B.C. and T.C. cloned FBXL19; B.B.C. assisted with animal experiments; C.Z. provided reagents; and R.K.Ma. assisted Y.Z. with direction and study design and provided reagents and editorial assistance with this manuscript.

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Correspondence to Yutong Zhao.

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Zhao, J., Wei, J., Mialki, R. et al. F-box protein FBXL19–mediated ubiquitination and degradation of the receptor for IL-33 limits pulmonary inflammation. Nat Immunol 13, 651–658 (2012). https://doi.org/10.1038/ni.2341

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