Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated antiviral signal transduction

Michaela U. Gack, Axel Kirchhofer, Young C. Shin, Kyung Soo Inn, Chengyu Liang, Sheng Cui, Sua Myong, Taekjip Ha, Karl Peter Hopfner, Jae U. Jung

Research output: Contribution to journalArticlepeer-review


The caspase recruitment domain (CARD) of intracellular adaptors and sensors plays a critical role in the assembly of signaling complexes involved in innate host defense against pathogens and in the regulation of inflammatory responses. The cytosolic receptor retinoic acid-inducible gene-I (RIG-I) recognizes viral RNA in a 5′-triphosphate-dependent manner and initiates an antiviral signaling cascade. Upon viral infection, the N-terminal CARDs of RIG-I undergo the K63-linked ubiquitination induced by tripartite motif protein 25 (TRIM25), critical for the interaction of RIG-I with its downstream signaling partner MAVS/VISA/IPS-1/Cardif. Here, we demonstrate the distinct roles of RIG-I first and second CARD in TRIM25-mediated RIG-I ubiquitination: TRIM25 binds the RIG-I first CARD and subsequently ubiquitinates its second CARD. The T55I mutation in RIG-I first CARD abolishes TRIM25 interaction, whereas the K172R mutation in the second CARD eliminates polyubiquitin attachment. The necessity of the intact tandem CARD for RIG-I function is further evidenced by a RIG-I splice variant (SV) whose expression is robustly up-regulated upon viral infection. The RIG-I SV carries a short deletion (amino acids 36-80) within the first CARD and thereby loses TRIM25 binding, CARD ubiquitination, and downstream signaling ability. Furthermore, because of its robust inhibition of virus-induced RIG-I multimerization and RIG-I-MAVS signaling complex formation, this SV effectively suppresses the RIG-I-mediated IFN-β production. This study not only elucidates the vital role of the intact tandem CARD for TRIM25-mediated RIG-I activation but also identifies the RIG-I SV as an off-switch regulator of its own signaling pathway.

Original languageEnglish (US)
Pages (from-to)16743-16748
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number43
StatePublished - Oct 28 2008
Externally publishedYes


  • Alternative splicing
  • Innate immunity
  • Interferon

ASJC Scopus subject areas

  • General


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