Necroptosis is a form of necrotic cell death that requires the activity of the death domain-containing kinase RIP1 and its family member RIP3. Necroptosis occurs when RIP1 is deubiquitinated to form a complex with RIP3 in cells deficient in the death receptor adapter molecule FADD or caspase-8. Necroptosis may play a role in host defense during viral infection as viruses like vaccinia can induce necroptosis while murine cytomegalovirus encodes a viral inhibitor of necroptosis. To see how general the interplay between viruses and necroptosis is, we surveyed seven different viruses. We found that two of the viruses tested, Sendai virus (SeV) and murine gammaherpesvirus-68 (MHV68), are capable of inducing dramatic necroptosis in the fibrosarcoma L929 cell line. We show that MHV68-induced cell death occurs through the cytosolic STING sensor pathway in a TNF-dependent manner. In contrast, SeV-induced death is mostly independent of TNF. Knockdown of the RNA sensing molecule RIG-I or the RIP1 deubiquitin protein, CYLD, but not STING, rescued cells from SeV-induced necroptosis. Accompanying necroptosis, we also find that wild type but not mutant SeV lacking the viral proteins Y1 and Y2 result in the non-ubiquitinated form of RIP1. Expression of Y1 or Y2 alone can suppress RIP1 ubiquitination but CYLD is dispensable for this process. Instead, we found that Y1 and Y2 can inhibit cIAP1-mediated RIP1 ubiquitination. Interestingly, we also found that SeV infection of B6 RIP3 mice results in increased inflammation in the lung and elevated SeV-specific T cells. Collectively, these data identify viruses and pathways that can trigger necroptosis and highlight the dynamic interplay between pathogen-recognition receptors and cell death induction.
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.
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