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these unconventional interactions, which disturbs the intracellular trafficking of
important viral regulatory proteins, may constitute a novel and attractive principle
for antiviral therapy.
Introduction
A defining feature of the eukaryotic cell is its division into nucleoplasm and
cytoplasm by a nuclear envelope. This segregation requires specific mechanisms for
the continuous transport of large numbers of macromolecules between both com-
partments. The only conduit between these two compartments are the nuclear pore
complexes (NPC), which serve as gatekeepers of the cell nucleus. These are aqueous
pores with a diameter of 25-30 nm that allow the free passage of small molecules
such as water, ions, nucleotides and small proteins (< 40 kDa) but act as an efficient
barrier for macromolecules such as proteins, RNA and DNA (Nakielny and Dreyfuss
1999). The mammalian NPC is a large proteinaceous structure of approximately
125 MDa, consisting of 30-35 different proteins termed nucleoporins (Nups)
(Reichelt et al. 1990; Cronshaw et al. 2002). Generally, the tightly regulated passage
of macromolecules (alternatively called cargos) through the NPC is carried out by a
mobile transport machinery that interacts with the NPC and is selective for specific
macromolecules (Gorlich and Kutay 1999). The transport receptors by themselves
shuttle between the nucleus and the cytoplasm and are able to recognize and bind
cargo molecules via specific recognition sequences.
Viruses, in particular those that replicate within the nucleus, have developed
various strategies to target the cellular machinery for nucleocytoplasmic exchange
(Cullen 2003; Gustin 2003; Fontoura et al. 2005). Several reasons appear to explain
the obvious endeavor of viruses to capitalize on these cellular transport pathways.
First, viruses have to ensure efficient nuclear import of viral proteins that are neces-
sary within the nucleus to support replication. Second, nuclear export must be opti-
mized, in particular for cargos that differ in structure from typical cellular cargos
(e.g., viral RNAs). In this regard, it should be mentioned that research on viruses
contributed significantly to the characterization of the major cellular nuclear export
pathways (TAP-dependent mRNA export pathway, CRM1/exportin1-dependent
pathway) (Cullen 2003). Third, some viruses even block the nucleocytoplasmic
transport of cellular molecules. For instance, this has been shown for the vesicular
stomatitis virus matrix and the influenza virus NS1 proteins. This is either used as
a strategy to compromise host cellular functions or even as a means to impair innate
and adaptive immune responses (Faria et al. 2005; Satterly et al. 2007).
Many viral macromolecules have evolved recognition sequences (e.g., nuclear
localization signals) that resemble cellular signals and thus allow for conventional
interactions with cellular transport receptors. Alternatively, however, several uncon-
ventional interactions have also been described that either help a specific viral com-
ponent to gain access or to modulate the nucleocytoplasmic exchange apparatus of
the cell. In this review, we focus on two human cytomegalovirus encoded proteins,
