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PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4

Nature Immunology volume 10, pages 1300–1308 (2009)Cite this article

Abstract

MAVS is critical in innate antiviral immunity as the sole adaptor for RIG-I-like helicases. MAVS regulation is essential for the prevention of excessive harmful immune responses. Here we identify PCBP2 as a negative regulator in MAVS-mediated signaling. Overexpression of PCBP2 abrogated cellular responses to viral infection, whereas knockdown of PCBP2 exerted the opposite effect. PCBP2 was induced after viral infection, and its interaction with MAVS led to proteasomal degradation of MAVS. PCBP2 recruited the HECT domain–containing E3 ligase AIP4 to polyubiquitinate and degrade MAVS. MAVS was degraded after viral infection in wild-type mouse embryonic fibroblasts but remained stable in AIP4-deficient (Itch−/−) mouse embryonic fibroblasts, coupled with greatly exaggerated and prolonged antiviral responses. The PCBP2-AIP4 axis defines a new signaling cascade for MAVS degradation and 'fine tuning' of antiviral innate immunity.

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Figure 1: PCBP2 interacts with MAVS and negatively regulates MAVS-mediated signaling.
Figure 2: PCBP2 negatively regulates cellular antiviral responses.
Figure 3: Characterization of the interaction between PCBP2 and MAVS.
Figure 4: PCBP2 induces the degradation of MAVS.
Figure 5: PCBP2 WB2 sequence is critical for MAVS degradation.
Figure 6: AIP4 is the E3 ubiquitin ligase for MAVS.
Figure 7: AIP4 negatively regulates RLH-mediated signaling.

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Acknowledgements

We thank D. Chen and D. Gao (Peking University) for technical assistance and the 293 cDNA library for yeast two-hybrid screening; Z. Chen (University of Texas Southwestern Medical Center) for MAVS chimera expression vectors; E. Harhaj (University of Miami) for Itch−/− MEFs; Q. Chen (Nankai University) for antibody to Bcl-xL (anti-Bcl-xL); H. Shu (Wuhan University) for HA-UB(K48) and HA-UB(K63) (plasmids encoding ubiquitin-K48 and ubiquitin-K63); C. Zheng (Wuhan University) for SeV; and C. Wang (Shanghai Institutes for Biological Sciences) for green fluorescent protein (GFP)-tagged NDV. Supported by the National Natural Science Foundation of China (30772024, 30721064), the National Basic Research Program of China (2007CB914502) and the Key Project of the Chinese Ministry of Education (108002).

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Authors and Affiliations

  1. The Education Ministry Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China

    Fuping You, Hui Sun, Xiang Zhou, Wenxiang Sun, Shimin Liang, Zhonghe Zhai & Zhengfan Jiang

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  1. Fuping You
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  2. Hui Sun
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Contributions

Z.J. designed research; F.Y., H.S., X.Z., W.S. and S.L. did research; Z.Z. contributed new reagents and analytical tools; F.Y., H.S., X.Z., W.S. and Z.J. analyzed data; and F.Y., X.Z. and Z.J. wrote the paper.

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Correspondence to Zhengfan Jiang.

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You, F., Sun, H., Zhou, X. et al. PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat Immunol 10, 1300–1308 (2009). https://doi.org/10.1038/ni.1815

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