Rotavirus interactions with innate signaling pathways.

<p>Viral nucleic acids may be recognized in a host cell by membrane-bound Toll-like receptors (TLR3) or cytoplasmic RIG-I-like receptors (RLRs). When activated by nucleic-acid binding, RLRs recruit and activate the signaling adaptor molecule IPS-1, which recruits a signaling complex that activates latent cytoplasmic transcription factors such as interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB). TLR3 activation stimulates the recruitment of the adaptor TRIF, which acts as a platform for a variety of signaling molecules that also phosphorylate IRF3 or NF-κB. When signaled, the C-terminus of IRF3 is phosphorylated, causing a conformational change that leads to dimerization and nuclear translocation. NF-κB is held inactive by inhibitor of NF-κB (IκB). Signals generated during viral infection cause phosphorylation of IκB, followed by ubiquitination (orange circles) and proteasomal degradation mediated by the SKP-CUL-F-box-β-TrCP (SCF^β-TrCP) E3 ubiquitin ligase complex. NF-κB subsequently translocates to the nucleus. IRF3 and NF-κB bind to the IFN-β promoter in a cooperative manner with c-Jun/ATF-2 forming an enhanceosome complex initiating the transcription of IFN-β mRNA. Additional transcription factors, including IRF7, are induced by IFN-β and can also bind to the IFN-β promoter to enhance the transcription of IFN-β and IFN-α genes. PI3K activity may be required for mediating TLR3 and RIG-I signaling by an unknown mechanism (dashed line). PKR responds to dsRNA binding by phosphorylating eIF2α, which ultimately inhibits translation initiation. PKR is also thought to promote the secretion of IFN-β by an unknown mechanism (dashed line). Rotavirus can antagonize innate signaling pathways through several avenues (shown in red), the primary one representing the NSP1-induced degradation of IRF3 and IRF7. Some NSP1 proteins are also known to induce the degradation of β-TrCP. Rotavirus NSP3 can also impede antiviral responses by suppressing the translation of host mRNAs generated from IFN-stimulated genes. By sequestering viral RNAs within viroplasms, the virus can prevent their recognition by PKR, RIG-I, MDA-5, and other sensors that upregulate antiviral responses.