The interaction of viral nucleic acids with PRRs leads to the activation of IFN regulatory factors (IRFs) and nuclear factor (NF)-B, which translocate from the cytoplasm to the nucleus where they stimulate transcription of type I IFN genes. (ISGs), which play crucial roles not only in the innate immune response, but also in B-cell and T-cell activation, cell cycle regulation, and apoptosis [1,2]. ISGs can interfere with viruses at various stages of their replicative cycle. To counteract the innate immune response, most viruses have evolved mechanisms to subvert IFN signaling, including rotaviruses (RVs), members of theReoviridaefamily. RV antagonizes the IFN induction pathway through the action of the nonstructural protein NSP1, which induces the proteasomal degradation of one or more transcription factors necessary for the efficient expression of type I IFN (Physique 1). == Physique 1. == RU 24969 Summary of NSP1 inhibition of the innate immune response pathway. Activation of dsRNA sensors in the cytoplasm (such as RIG-I) or bound to membranes (such as TLR3) stimulates pathways that result in the phosphorylation of IRF3 and IRF7 by IKK- SCDO3 and TBK1. Phosphorylation allows for the formation of IRF3 homodimers, IRF7 homodimers, or IRF3/IRF7 heterodimers. RIG-I activation also results in the ubiquitination (Ub) of IB by the E3 ligase Skp1/Cul1/F-box complex SCF-TrCPand subsequent degradation by the proteasome. Degradation of IB frees the NF-B complex (p50 and p65), which moves to the nucleus. The binding of NF-B and IRF dimers to the IFN- RU 24969 promoter results in transcription and secretion of IFN-, which binds to type I IFN receptors (IFNAR). IFNAR signals the ISGF3 complex, consisting of STAT1, STAT2, and IRF9, to produce additional IRF7 and type I IFNs, thus amplifying the IFN response. The NSP1 protein from different RVs has a range of activities. Some RV NSP1 proteins inhibit the type I IFN response by degrading IRF3 and IRF7, while at least one NSP1 prevents type I IFN induction by degrading -TrCP and preventing the nuclear translocation of NF-B. == IFN Response to Viral Contamination == The IFN response can be brought on in virus-infected cells by the conversation of viral nucleic acids or proteins with pattern-recognition receptors (PRRs). Two families of PRRs have been identified as primary sensors of viral contamination: RU 24969 the transmembrane TLRs (Toll-like receptors) and the cytoplasmic pathogen detectors, including the RNA sensors RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5), and the DNA sensor DAI (DNA-dependent activator of IFN-regulatory factors) [35]. RU 24969 The conversation of viral nucleic acids with PRRs leads to the activation of IFN regulatory factors (IRFs) and nuclear factor (NF)-B, which translocate from the cytoplasm to the nucleus where they stimulate transcription of type I IFN genes. Collectively, IFN expression requires the participation of several transcription factors, providing viruses many potential targets for antagonizing the IFN signaling pathway [6]. Members of the IRF family of proteins include IRF3 and IRF7, key regulators of type I IFN expression [7]. IRF3 is usually constitutively expressed in cells where it accumulates at elevated levels in the cytoplasm. In contrast, IRF7 is present in most cells at very low levels, and its expression is usually amplified by type I IFN [7,8]. Both IRF3 and IRF7 reside in an inactive state in the cytoplasm and are activated by phosphorylation of residues in the C-terminal regulatory region by the kinases TBK1 or IKK- [9,10]. Phosphorylated IRF3 and IRF7 form homodimers or heterodimers, which then translocate to the nucleus. IRF3 homodimers, IRF7 homodimers, and IRF3/IRF7 heterodimers have differential effects around the.