The export of proteins, transfer RNA molecules and ribosomal subunits from
the nucleus to the cytoplasm appears to operate by similar mechanisms to
that described above for nuclear import. The export of mRNA molecules, how-
ever, seems to involve an mRNA exporter protein that directs their passage
through the NPCs.
Clinical Aspects of Nucleocytoplasmic Transport
Given that NPCs are the pivotal junctions between the cytoplasm and
the nucleus, they are closely involved in the pathology of viral infections
(Chapter 2). Virus particles fuse with the plasma membrane or are taken up
into the cells by endocytosis. However, they must leave the cytoplasm and
enter the nucleus. For example, the hepatitis B virus (HBV ) has a capsid of
diameter 32–36 nm and is small enough to cross the NPC directly. In vivo,
phosphorylation of HBV capsids makes their NLSs accessible to the nuclear
transport machinery. Following their transport through the central pore of
the NPC, capsid protein and DNA from mature viruses are released into the
nucleoplasm. In contrast, adenovirus particles and herpes simplex virus
(HSV ) have capsids with diameters of 90 nm and 125 nm respectively that
are too large to traverse the NPC. These virus particles dock at the cyto-
plasmic side of the NPC in an importin dependent manner. The HSV then
releases its DNA through the NPC into the nucleoplasm. Adenovirus parti-
cles, however, first trap a variety of transport factors that are necessary for
the subsequent disassembly of the capsid before the translocation of the
viral DNA into the nucleus is possible.
Malfunctions of nucleocytoplasmic transport are associated with a number of
diseases including Huntington’s disease (Chapter 15). In Huntington’s disease,
a single gene is mutated and the corresponding protein, huntingtin, accu-
mulates in the nucleus rather than in the cytoplasm. Nuclear pore complexes
have also been implicated in several autoimmune diseases (Chapter 5) that
are caused by autoantibodies recognizing proteins of the NPCs. This con-
tributes to a number of diverse illnesses, such as systemic lupus erythema-
tosus, rheumatoid arthritis and primary biliary cirrhosis. Nucleoporins have
been implicated in several types of cancers (Chapter 17). In some cases, these
are associated with the overexpression of NPC proteins, but in most other
cases tumorigenesis stems from chromosomal rearrangements that result in
oncogenic fusion proteins. Examples include tumors such as acute myeloid
leukemia, adenocarcinoma, chronic myeloid leukemia, inflammatory myofi-
broblastic tumor, myeloblastic leukemia, osteosarcoma and papillary thy-
roid carcinomas, which affect a variety of tissues. At least 11 chromosomal
rearrangements in acute leukemia involve genes that encode nuclear pore
proteins; nine of these involve a single protein called nucleoporin 98. Some
studies have suggested that the density of NPCs in aneuploid bladder tumors
that have cells with abnormal numbers of chromosomes is significantly higher
than in normal cells.
16.3 Plasma Membrane Disorders
Numerous clinical conditions are associated with defective receptors of the
plasma membrane and/or subsequent defective signal transduction or defec-
tive transport of materials across the membrane. Defects of receptor proteins
and signal transduction can result in the development of cancerous states
(Chapter 17), while cases of type 2 diabetes are associated with an ineffec-
tive insulin receptor (Chapter 7). Familial hypercholesterolemia, which was
described in Chapter 14, arises from defective receptors for LDL particles.
The rare Tangier disease mentioned in Chapter 14 is caused by mutations
in the gene for cholesterol transport protein of the plasma membrane. This
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