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Figure 1. Retinoic acid-inducible gene-I-mediated type I interferon pathway and its regulation during influenza A virus infection. (A--E) Critical checkpoints. (A) Virus replication produces triphosphorylated vRNA and potentially dsRNA byproducts that are pathogen-associated molecular patterns recognized by cytoplasmic RIG-I. (B) NS1 regulates the activation of RIG-I by binding to and sequestering dsRNA and/or by interaction with RIG-I. Formation of viral RNP complexes may also contribute to ''hiding'' pathogen-associated molecular patterns from RIG-I. (C) Binding of NS1 to TRIM25 prevents essential ubiquitination of RIG-I. (D) Cap-snatching activity of the viral polymerase complex may reduce the pool of host antiviral mRNAs available for nuclear export and translation. The NS1 protein also directly inhibits global cellular pre-mRNA processing by binding to host CPSF30. (E) NS1 binds to components of the nuclear pore complex and inhibits nuclear export of cellular mRNA. CPSF30: 30-kDa cleavage and polyadenylation specificity factor; IRF: Interferon regulatory factor; MAVS: Mitochondrial antiviral signaling adaptor; NEMO: NF-kκB essential modulator; NS1: Nonstructural protein 1; PPP: Triphosphate; RIG: Retinoic acid-inducible gene; RIP: Receptor-interacting protein; RNP: Ribonucleoprotein; TANK: TRAF family member-associated NF-kκB activator; TRAF: TNF-receptor-associated factor; TRIM: Tripartite motif; Ub: Ubiquitin.
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Figure 2. Type I interferon receptor signaling pathway and expression of interferon-stimulated genes. Binding of IFN-αα/bβ to the IFN receptor stimulates the phosphorylation of STAT1 and STAT2. Phosphorylated STAT1 and 2 associate with IRF-9 to form the transcription factor ISGF3, which relocalizes to the nucleus and stimulates the transcription of ISGs whose promoters contain IFN-stimulated response elements. Although IFN stimulates the transcription of more than 300 ISGs, only the antiviral functions of a small percentage have been well characterized. Notable examples of IFN-induced antiviral effectors and their regulation by influenza viruses are indicated. See text for further details. A/NS1: Influenza A virus NS1 protein; B/NS1: Influenza B virus NS1 protein; IFN: Interferon; IRF: IFN regulatory factor; ISG: IFN-stimulated gene; MxA: Myxovirus resistance gene A; NP: Nucleocapsid protein; NS1: Nonstructural protein 1; OAS: 2´´-5´´ oligoadenylate synthetase; SOCS: Suppressor of cytokine signaling.
(Figure omitted. See article PDF.)
Figure 3. Potential multifunctional antiviral target on the influenza A virus NS1 protein. (A) Surface representation of an NS1 ED monomer (dark gray) in complex with a fragment of CPSF30 (light gray, cartoon ribbon representation). Aromatic residues of...