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

• The TRIM25 RING domain dimerizes to make polyubiquitin chains and ubiquitinate RIG-I
• RING domain dimerization is facilitated by higher-order oligomerization of TRIM25
• Higher-order oligomerization of TRIM25 is facilitated by binding to RIG-I 2CARD
• Cooperative assembly of TRIM25 and RIG-I facilitates antiviral signaling

SummaryAntiviral 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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