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

Cell Rep 2016 08 14;16(5):1315-1325. Epub 2016 Jul 14.

Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076470PMC
http://dx.doi.org/10.1016/j.celrep.2016.06.070DOI Listing
August 2016
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