TRIM25 RING-FINGER UBIQUITIN LIGASE RIG-I MEDIATED ANTI-VIRAL ROLE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Retinoic acid inducible gene-I (RIG-I) is a cytoplasmic RNA receptor that recognizes viral RNAs and initiates type I interferon (IFN)-mediated host protective innate immunity against viral infection. In addition, members of the tripartite motif (TRIM) protein family that contains a cluster of RING-finger domain, B-box/coiled-coil domain (B Box/CCD), and SPRY domain are involved in various cellular processes, including cell proliferation and anti-virus. Here, we report that the N-terminal caspase recruitment domains (CARDs) of RIG-I undergoes a robust ubiquitination induced by TRIM25 protein, also known as estrogen-responsive RING-finger protein (Efp). The C-terminal SPRY domain of TRIM25 interacts with the N-terminal CARD of RIG-I and this interaction effectively delivers the Lys 63-linked ubiquitin moiety to the N-terminal CARD of RIG-I, which consequently results in marked increase of RIG-I downstream signaling activity. RIG-I Lys-172 (K172) residue is critical for TRIM25-mediated ubiquitination as well as its ability to induce anti-viral signal transduction. Furthermore, gene targeting demonstrates that TRIM25 is essential not only for RIG-I ubiquitination but also for RIG-I mediated IFN-betta production and anti-viral activity in response to RNA virus infection. AIDS related.