Proposed mechanism of 4b action in MERS-CoV infection.

<p>In WT MERS-CoV infection, 4b protein with an intact NLS binds KPNA4 for nuclear translocation thereby outcompeting NF-κB binding to KPNA4, which retains NF-κB in the cytoplasm and inhibits the expression of NF-κB-dependent pro-inflammatory cytokines. In contrast, in the absence of 4b (MERS-CoV-Δ4b) or in the presence of cytoplasmic 4b NLS-mutants (MERS-CoV-4b-mNLS), which do not bind KPNA4, NF-κB is imported into the nucleus by KPNA4, where it binds to DNA κB sites to promote the expression of pro-inflammatory cytokines (TNF-α, IL-6 and IL-8).