Viral Targeting of Importin Alpha-Mediated Nuclear Import to Block Innate Immunity

Figures

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  Figure 1. Overview of the Canonical Nuclear Import Mechanism. The nuclear cargo (highlighted in orange) harbors a nuclear localization signal (NLS) (depicted in yellow). The NLS is bound by importin-α (colored blue), and importin-β (shown in green) binds importin-α through the IBB domain. The trimeric assembly translocates through the nuclear pore complex into the nucleus, where upon entry, RanGTP (colored black) binds importin-β, mediating disassembly of the complex and the release of cargo.

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  Figure 2. Classification of Human Importin Alpha Isoforms The seven human importin alpha isoforms are grouped into three subfamilies (SF-1, SF-2, and SF-3) according to their sequence similarities. Subfamily SF-1 includes IMPA1 and IMPA8, which exhibit the lowest sequence identity among the subfamilies. Subfamily SF-2, with the highest sequence homology, consists of IMPA3 and IMPA4. Subfamily SF-3 comprises IMPA5, IMPA6, and IMPA7. The specific sequence identity percentages, calculated using BLAST, are indicated for each isoform to the right of the figure.

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  Figure 3. Ebola VP24 inhibits STAT1 signaling by binding SF-3 IMPAs. (A) IMPAs are comprised of 10 armadillo (ARM) repeats of 3 helices (PDB 1BK5). cNLS and ncNLS sites are indicated. (B) VP24 functions as a competitive inhibitor of STAT1-IMPA interaction by blocking phosphorylated STAT1 (PY-STAT1) binding via its ncNLS to IMPA (PDB 1BK5, 4U2X, and 1BF5).

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  Figure 4. Interactions and Structural Insights into MERS-CoV ORF4b Inhibition of Immune Signaling. Normally, an immune stimulus would trigger the NF-B pathway, leading to the transport of p50/p65 into the nucleus. The complex of IMPA2 with p50/p65, which facilitates this process, has been structurally characterized (PDB 7LET). The MERS-CoV ORF4b protein can disrupt this interaction, thereby preventing the nuclear import of p50/p65 and suppressing the expression of ISGs and IFNs. Structural analysis has provided insights into the MERS-CoV ORF4b mode of action by revealing a mutually exclusive binding mechanism at the interface, as shown in the structural data from PDB 7RFZ [44]. In the visualization, IMPA is rendered in green with a surface representation, while p50 and p65 are depicted in stick form in salmon and light blue, respectively. These models are constructed based on high-resolution X-ray crystallography data.