FAS-associated death domain and tripartite motif-containing protein 21 negatively regulate virus-induced interferon production (P6126)

Abstract

Abstract While induction of type I Interferon (IFN) during the host antiviral response is imperative for efficient viral clearance, regulation of this response is crucial for immune system homeostasis. We have reported that FADD, a well characterized apoptotic protein, is involved in negatively regulating RNA virus-induced IFN-α production through a novel interaction with the E3 ubiquitin ligase, Tripartite Motif-Containing Protein 21 (TRIM21). Interaction between FADD and TRIM21 cooperatively represses IFN-α activation in Sendai virus infected cells. This occurs through TRIM21 targeted ubiquitin-mediated degradation of transcription factor IRF7. Recently, it was also determined that FADD and TRIM21 can be found in 2 different complexes within cells: one containing FADD/TRIM21/IRF7 and a second containing FADD/TRIM21/RIP1 (receptor-interacting protein 1). We hypothesized that TRIM21 may have different functions dependent on complex composition and that its activity could be regulated via its autoubiquitination status. Interaction of TRIM21 with FADD yields increased autoubiquition while interaction with RIP1 yields decreased autoubiqtuitination suggesting a regulation mechanism. However, studies involving mutant forms of TRIM21 which lack autoubiquitination demonstrate that autoubiquitination status does not regulate TRIM21’s ability to target IRF7 for degradation. We are currently investigating the function of TRIM21 in other FADD/RIP1 dependent processes like cell death.