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Figure 4

Figure 4. IFIT proteins recognize the 5’-ppp of viral RNA and inhibit infection. From: The broad-spectrum antiviral functions of IFIT and IFITM proteins.

Viral infection by negative-stranded RNA viruses (such as RVFV, VSV or influenza A virus) generates uncapped 5’-ppp on their single- or double-stranded RNA. These are recognized by cytoplasmic sensors (RIG-I and MDA5), which induce the expression of IFN-stimulated genes (ISGs) including IFIT1, IFIT2 and IFIT3, by both IFNβ-dependent and -independent (for example, IRF3-dependent) pathways. IFIT1 functions as a sensor of viral RNA containing the 5’-ppp, resulting in assembly of an IFIT1–IFIT2–IFIT3 complex. This presumably inhibits viral infection by sequestering RNA (or promoting degradation) of the actively replicating pool. Data are conflicting as to whether IFIT proteins also promote or inhibit the host inflammatory response, possibly by changing the relative amount of viral RNA in the cell with free 5’-ppp ends. Part of this figure is adapted from a prior publication 81.

Michael S. Diamond, et al. Nat Rev Immunol. 2013 January;13(1):46-57.
Figure 5

Figure 5. Proposed topologies and sequence alignment of IFITM orthologues and paralogues. From: The broad-spectrum antiviral functions of IFIT and IFITM proteins.

Two topologies of IFITM proteins have been proposed. In the first model, the amino and carboxyl termini are located in the lumen of IFITM-containing vesicles, and the hydrophobic regions fully traverse the membrane (top left). Yount et al65 have proposed an alternative model in which both termini are oriented toward the cytoplasm, and hydrophobic domains are embedded in the membrane without traversing it (top right). A yellow dot in both models indicates the site of a palmityl group that is important for protein stability and restriction activity 64. (Bottom) An alignment of human, mouse and chicken IFITM proteins is shown. Red indicates conservation of a residue in at least nine of the twelve IFITM proteins shown. Note that the conservation of the first transmembrane domain and the cytoplasmic domain is based on the first topology model. The site of palmityl addition is highlighted in yellow. Green and cyan indicate species-specific signature residues of human and mouse, respectively, possibly suggesting interaction with a cofactor that similarly diverged in each species.

Michael S. Diamond, et al. Nat Rev Immunol. 2013 January;13(1):46-57.
Figure 6

Figure 6. Correlation between the site of virus fusion and susceptibility to IFITM-mediated restriction. From: The broad-spectrum antiviral functions of IFIT and IFITM proteins.

Viruses fuse with host cell membranes in different compartments within the endocytic pathway, and IFITM-mediated restriction activity correlates with the site of fusion. For example, arenaviruses such as Junin and Machupo viruses, follow the recycling pathway of their common receptor, transferrin receptor 1 82. These viruses are not susceptible to IFITM-mediated restriction. By contrast, viruses such as influenza A virus fuse in late endosomes and are restricted by IFITM proteins, particularly by IFITM372. Viruses such as SARS coronavirus (SARS-CoV) and Ebola virus depend on lysosomal cathepsins and other lysosome-resident proteins, and are more restricted by IFITM1 74. Murine IFITM6 is more specialized and restricts the entry of Ebola virus and SARS-CoV, but not influenza A virus. Trypsin treatment of SARS-CoV allows it to fuse at the plasma membrane and bypass IFITM-mediated restriction. Retroviruses pseudotyped with entry proteins from these viruses show identical patterns of restriction, implicating the entry process in the antiviral activity of IFITM proteins. Note that the diagram is schematic and ignores much of the diversity of cellular compartments and complexity of cellular trafficking.

Michael S. Diamond, et al. Nat Rev Immunol. 2013 January;13(1):46-57.
Figure 2

Figure 2. Genomic relationship and structure of IFIT genes. From: The broad-spectrum antiviral functions of IFIT and IFITM proteins.

A. A phylogram showing relationships between different species of IFIT genes. All full-length IFIT protein sequences for eight species (human, mouse, rat, chimpanzee, dog, frog, toad and salmon) were obtained from the NCBI database. IFIT-like and duplicate amino acid sequences were removed manually or with ElimDupes (www.hiv.lanl.gov). Amino acid alignments were generated using CLC Main Workbench. A tree was created from the alignment using the Neighbor Joining method and 1,000 bootstrap replicates. The scale of branch length is shown below the tree. B. Scheme of tetratricopeptide repeats (TPR) in different IFIT proteins from humans and mice. Pink boxes indicate TPR motifs according to the consensus sequence and structural definition 19. This diagram is adapted from a prior review on virus-induced immune genes 22. C. Cartoon diagram of the structure of the IFIT2 monomer (PDB 4G1T). α-helical structural elements are shown as cylinders. The N-terminal region (blue), domain-swapped region (green) and C-terminal region (yellow) are labeled. The RNA binding region is located in the C-terminus and is labeled in red (residue K410). The figure was prepared with PyMOL (http://pymol.org/) and is adapted from the original publication 20.

Michael S. Diamond, et al. Nat Rev Immunol. 2013 January;13(1):46-57.
Figure 3

Figure 3. IFIT proteins function as antiviral molecules by inhibiting distinct steps in the translation of viral mRNA. From: The broad-spectrum antiviral functions of IFIT and IFITM proteins.

(Top left, boxed) IFIT proteins bind subunits of the eIF3 multi-subunit complex that regulates translation initiation. Human IFIT1 and IFIT2 bind eIF3e and human IFIT2, mouse IFIT1 and mouse IFIT2 bind eIF3c. (Right) Scheme of translation initiation and the steps putatively blocked by IFIT family members. To begin translation in mammalian cells, a free pool of 40S ribosomal subunits is stabilized by eIF3 and binds to the ternary complex (eIF2–GTP–Met-tRNA) in the presence of eiF1 (not shown). This allows assembly of the 43S pre-initiation complex, which then binds mRNA that is capped and methylated at the N-7 and 2’-O positions. This interaction is stabilized by eIF4E and eIF4G, which results in the formation of the 43S–mRNA complex, which is competent for AUG (start codon) scanning and translation. For HCV genomic mRNA with an internal ribosome entry site (IRES), association with eIF4E and eiF4G or other cap-binding factors is not required to stabilize the 43S–mRNA complex. a-c. IFIT-mediated inhibition of translation based on published data 27, 37, 38, 40, 41: (a) IFIT1 and IFIT2 binding to eIF3e blocks binding of eIF3e to the ternary complex (eIF2–GTP– Met-tRNA); (b) Binding of human IFIT2, and mouse IFIT1 and IFIT2, to eIF4c blocks formation of the 43S pre-initiation complex; (c) Human IFIT1 binding to eIF3 blocks HCV IRES recognition of the 43S complex. Disruption of eIF3 binding to the HCV IRES also can prevent eIF2 recruitment and suppresses ternary complex formation. d-e. Possible mechanisms for mouse IFIT1-mediated inhibition of viral RNA lacking 2’-O methylation. (d) IFIT1 directly recognizes the type 0 cap structure (no 2’-O methylation) on viral RNA and prevents its binding to the 43S pre-initiation complex; or (e) IFIT1 binding to eIF3 preferentially prevents formation of the 43S–mRNA complex for RNA containing type 0 cap structures.

Michael S. Diamond, et al. Nat Rev Immunol. 2013 January;13(1):46-57.
Figure 1

Figure 1. Detection of pathogen RNA and DNA in the cytoplasm and activation of IFN-β and ISGs. From: The broad-spectrum antiviral functions of IFIT and IFITM proteins.

IFIT and IFITM genes are induced by host innate immune defenses after pathogen infection. The figure shows a scheme of innate immune signaling triggered by viral infection through cytosolic RIG-I-like receptors (RLRs; MDA5 and RIG-I), cytosolic DNA sensors (DAI, IFI16, DHX9 and DHX36) and endosomal Toll-like receptors (TLR3, TLR7 and TLR9). Black and blue lines indicate the responses that are specific for viral RNA and DNA, respectively, and red lines are shared responses. The bold red line indicates that phosphorylated IRF3 can activate the expression of interferon (IFN)-stimulated genes (ISGs; such as IFIT and IFITM genes) independently of IFN signaling. P denotes phosphorylation; Ubq denotes ubiquitin modification. Infection by RNA viruses produces RNA intermediates in the cytosol and endosome that are detected as non-self by RIG-I and MDA5, and by TLR3 and TLR7, respectively. The RLR’s interact with MAVS leading to the recruitment of TRAF3, TBK1 and IKKε, or of NEMO (IKKγ), IKKα and IKKβ, which results in activation and nuclear translocation of IRF3 and NF-κβ, respectively. TLRs interact with TRIF or MyD88, leading to the activation of IRF3 or IRF7. IRF3, IRF7 and NF-κβ bind the IFNβ gene promoter and induce transcription. Secretion of IFNβ by the infected cells results in paracrine type I IFN signaling through IFNAR, which induces hundreds of ISGs (not shown in Figure). Intracellular DNA is generated from viral infection, bacteria infection or the phagocytosis of dead cells. TLR9 recognizes CpG DNA in the endosome and activates MYD88. Binding of DNA by DAI or IFI16 results in STING-dependent activation of IRF3 and NF-κβ. RNA polymerase III converts DNA into short RNA containing a 5’-ppp, which is a ligand for RIG-I recognition. DHX9 and DHX36 bind DNA ligands (CpG-A and CpG-B) in the cytosol and induce MYD88- and IRF7-dependent responses.

Michael S. Diamond, et al. Nat Rev Immunol. 2013 January;13(1):46-57.

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