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

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.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [1] ;  [1] ;  [5] ;  [6] ;  [1]
  1. Univ. of Virginia, Charlottesville, VA (United States)
  2. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States)
  3. Univ. of Chicago, IL (United States)
  4. Univ. of Utah, Salt Lake City, UT (United States)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  6. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States); Univ. of Chicago, IL (United States)
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 16; Journal Issue: 5; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES
OSTI Identifier:
1399612
Alternate Identifier(s):
OSTI ID: 1379552