Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection

Abstract

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.

Roles of Nucleoporin RanBP2/Nup358 in Acute Necrotizing Encephalopathy Type 1 (ANE1) and Viral Infection

“…It is known that the production of cytokines requires the activation of innate immune pathways. These sense viral infections and stimulate downstream transcription factors, including interferon (IFN)-regulatory factor 3 (IRF3), IRF7, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB, consisting of p65 and p50), and signal transducer and activator of transcription (STAT) proteins [ 106 ]. In general, the hyperactivation of these signals can cause cytokine storms.…”

“…This is thought to initiate viral DNA uncoating and promote the release of viral DNA into the nucleoplasm. Since RanBP2 is in close proximity to Nup214, it is believed that they constitute a platform for the attachment of HSV-1 capsids to the cytoplasmic face of the nuclear pore [ 106 , 113 ]. Although RanBP2 is known to play a critical role in docking HSV capsids to the NPC, there are few reports of HSV infection triggering ANE1.…”

Nuclear Exportin 1 (XPO1) Binds to the Nuclear Localization/Export Signal of the Turnip Mosaic Virus NIb to Promote Viral Infection

“…The nucleocytoplasmic transport depends on a network of proteins that shuttle between the nucleus and cytoplasm, allowing substrate exchange through the nuclear pore complex (NPC). The NPC is a large, multi-subunit structure of ∼110–125 MDa in metazoans and consists of 8–64 copies of about 34 different nuclear pore proteins ( Knockenhauer and Thomas, 2016 ; Lin et al, 2016 ; Ungricht and Ulrike, 2017 ; Shen et al, 2021 ). The plant NPC has similar structure and components to metazoans or yeast ( Tamura et al, 2010 ; Tamura and Hara-Nishimura, 2013 ).…”

“…The “classical” active nuclear import pathway begins with a pair of nuclear import receptors importin α and importin β and is ferried across the pore ( Meier, 2005 ; Shen et al, 2021 ). In the cytoplasm, the importin α/β heterodimer using the NLS-binding region of importin α binds to a protein containing NLS.…”

“…Translocation into the nucleus requires recruitment of the GTP-bound small GTPase Ran (Ran-GTP) to importin β, which causes the disassembly of the import complex and releases the cargo. Furthermore, the complex of importin β and Ran-GTP is transported back to the cytoplasm, whereas importin α is recycled ( Shen et al, 2021 ). In addition to the members of the importin (Imp) superfamily, an ever-expanding repertoire of Imp-independent nuclear import pathways/mechanisms such as the calcium-binding protein calmodulin or through direct binding to the components of the NPC has been found ( Wagstaff and Jans, 2009 ).…”