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Cell Rep. 2016 Aug 2;16(5):1315-1325. doi: 10.1016/j.celrep.2016.06.070. Epub 2016 Jul 14.

Mechanism of TRIM25 Catalytic Activation in the Antiviral RIG-I Pathway.

Author information

1
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
2
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Microbiology, University of Chicago, Chicago, IL 60637, USA.
4
Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA.
5
Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
6
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Microbiology, University of Chicago, Chicago, IL 60637, USA. Electronic address: mgack@uchicago.edu.
7
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: opornillos@virginia.edu.

Abstract

Antiviral response pathways induce interferon by higher-order assembly of signaling complexes called signalosomes. Assembly of the RIG-I signalosome is regulated by K63-linked polyubiquitin chains, which are synthesized by the E3 ubiquitin ligase, TRIM25. We have previously shown that the TRIM25 coiled-coil domain is a stable, antiparallel dimer that positions two catalytic RING domains on opposite ends of an elongated rod. We now show that the RING domain is a separate self-association motif that engages ubiquitin-conjugated E2 enzymes as a dimer. RING dimerization is required for catalysis, TRIM25-mediated RIG-I ubiquitination, interferon induction, and antiviral activity. We also provide evidence that RING dimerization and E3 ligase activity are promoted by binding of the TRIM25 SPRY domain to the RIG-I effector domain. These results indicate that TRIM25 actively participates in higher-order assembly of the RIG-I signalosome and helps to fine-tune the efficiency of the RIG-I-mediated antiviral response.

PMID:
27425606
PMCID:
PMC5076470
DOI:
10.1016/j.celrep.2016.06.070
[Indexed for MEDLINE]
Free PMC Article

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