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The nuclear pore complex is the sole gateway connecting the nucleoplasm and cytoplasm. In humans, the nuclear pore complex is one of the largest multiprotein assemblies in the cell, with a molecular mass of ∼110 MDa and consisting of 8 to 64 copies of about 34 different nuclear pore proteins, termed nucleoporins, for a total of 1000 subunits per pore. Trafficking events across the nuclear pore are mediated by nuclear transport receptors and are highly regulated. The nuclear pore complex is also used by several RNA viruses and almost all DNA viruses to access the host cell nucleoplasm for replication. Viruses hijack the nuclear pore complex, and nuclear transport receptors, to access the nucleoplasm where they replicate. In addition, the nuclear pore complex is used by the cell innate immune system, a network of signal transduction pathways that coordinates the first response to foreign invaders, including viruses and other pathogens. Several branches of this response depend on dynamic signaling events that involve the nuclear translocation of downstream signal transducers. Mounting evidence has shown that these signaling cascades, especially those steps that involve nucleocytoplasmic trafficking events, are targeted by viruses so that they can evade the innate immune system. This review summarizes how nuclear pore proteins and nuclear transport receptors contribute to the innate immune response and highlights how viruses manipulate this cellular machinery to favor infection. A comprehensive understanding of nuclear pore proteins in antiviral innate immunity will likely contribute to the development of new antiviral therapeutic strategies.

Signal-dependent targeting of proteins into and out of the nucleus is mediated by members of the importin (IMP) family of transport receptors, which recognise targeting signals within a cargo protein and mediate passage through the nuclear envelope-embedded nuclear pore complexes. Regulation of this process is paramount to processes such as cell division and differentiation, but is also critically important for viral replication and pathogenesis; phosphorylation appears to play a major role in regulating viral protein nucleocytoplasmic trafficking, along with other posttranslational modifications. This review focuses on viral proteins that utilise the host cell IMP machinery in order to traffic into/out of the nucleus, and in particular those where trafficking is critical to viral replication and/or pathogenesis, such as simian virus SV40 large tumour antigen (T-ag), human papilloma virus E1 protein, human cytomegalovirus processivity factor ppUL44, and various gene products from RNA viruses such as Rabies. Understanding of the mechanisms regulating viral protein nucleocytoplasmic trafficking is paramount to the future development of urgently needed specific and effective anti-viral therapeutics. This article was originally intended for the special issue “Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import”. The Publisher apologizes for any inconvenience caused., Research highlights ► Nucleocytoplasmic trafficking of viral proteins is central to viral infection. ► Posttranslational modification is a key means to regulate viral protein trafficking. ► Nuclear trafficking of viral proteins can be a target for development of anti-virals.