Abstract
The transport of macromolecules into the cell nucleus occurs through nuclear pore complexes (NPCs) and is mediated by cellular receptors. Recently, a novel mechanism of nuclear entry, in which actin polymerization provides a propulsive force driving the transport through the NPC, has been proposed. This mechanism is used by the nucleocapsid from baculovirus, one of the largest viruses to replicate in the nucleus of their host cells, which crosses the NPC and enters the nucleus independently of cellular receptors. The baculovirus nucleocapsid contains a protein that hijacks the cellular actin polymerization machinery to assemble actin filaments that propel the nucleocapsid through the host cell cytoplasm. In this study, we functionalized carbon nanotubes by covalently attaching a protein domain responsible for inducing actin polymerization and investigated their nuclear entry. We found that the functionalized carbon nanotubes were able to enter the cell nucleus under permissive conditions for actin polymerization, but not when this process was inhibited. We conclude that the mechanical force generated by actin polymerization can drive cargo entry into the cell nucleus. Our results support a novel force-driven mechanism for molecular entry into the cell nucleus.
Highlights
Physiological transport of macromolecules from the cytosol into the nucleus occurs through specialized channels called nuclear pore complexes (NPCs) that span the double nuclear membrane [1]
To develop carbon nanotubes as molecular transporters that mimic the baculovirus nucleocapsid and its actin polymerization-inducing ability, the VCA domain that is common to all Wiskott–Aldrich syndrome protein (WASP) family proteins, including baculovirus VP78/83, was conjugated to multi-walled CNTs (MWCNTs) with diameters close to the baculovirus capsid diameter
bovine serum albumin (BSA) attachment to MWCNT was detected by immuno-gold labeling using an anti-BSA antibody, followed by negative staining and transmission electron microscopy (TEM) imaging
Summary
Physiological transport of macromolecules from the cytosol into the nucleus occurs through specialized channels called nuclear pore complexes (NPCs) that span the double nuclear membrane [1]. Proteins at the center of the NPC, called nuleoporins or Nups, act as gatekeepers and form a barrier that excludes molecules from the nucleus [2]. Ions and small molecules with diameters of up to 5 nm [3] can passively diffuse through the NPC. Proteins larger than this diffusion limit and up to 39 nm in diameter [4] may pass the NPC if they carry specific peptide sequences termed nuclear localization sequences (NLSs) [5].
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