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Sci. Signal., 13 November 2012
Vol. 5, Issue 250, p. ra81
[DOI: 10.1126/scisignal.2003152]

RESEARCH ARTICLES

Single Amino Acid Substitutions Confer the Antiviral Activity of the TRAF3 Adaptor Protein onto TRAF5

Peng Zhang1*, Anna Reichardt2*, Huanhuan Liang1*, Roghiyh Aliyari2, David Cheng2, Yaya Wang2, Feng Xu2, Genhong Cheng2{dagger}, and Yingfang Liu1{dagger}

1 State Key Laboratory of Biomacromolecules, CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
2 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.

* These authors contributed equally to this work.

Abstract: The TRAF [tumor necrosis factor receptor–associated factor] family of cytoplasmic adaptor proteins link cell-surface receptors to intracellular signaling pathways that regulate innate and adaptive immune responses. In response to activation of RIG-I (retinoic acid–inducible gene I), a component of a pattern recognition receptor that detects viruses, TRAF3 binds to the adaptor protein Cardif [caspase activation and recruitment domain (CARD) adaptor–inducing interferon-β (IFN-β)], leading to induction of type I IFNs. We report the crystal structures of the TRAF domain of TRAF5 and that of TRAF3 bound to a peptide from the TRAF-interacting motif of Cardif. By comparing these structures, we identified two residues located near the Cardif binding pocket in TRAF3 (Tyr440 and Phe473) that potentially contributed to Cardif recognition. In vitro and cellular experiments showed that forms of TRAF5 with mutation of the corresponding residues to those of TRAF3 had TRAF3-like antiviral activity. Our results provide a structural basis for the critical role of TRAF3 in activating RIG-I–mediated IFN production.

{dagger} To whom correspondence should be addressed. E-mail: gcheng{at}mednet.ucla.edu (G.C.); liuy{at}ibp.ac.cn (Y.L.)

Citation: P. Zhang, A. Reichardt, H. Liang, R. Aliyari, D. Cheng, Y. Wang, F. Xu, G. Cheng, Y. Liu, Single Amino Acid Substitutions Confer the Antiviral Activity of the TRAF3 Adaptor Protein onto TRAF5. Sci. Signal. 5, ra81 (2012).

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