Biology Reference
In-Depth Information
mediated via a signal sequence that is clearly distinct from the NLS. The best
characterized nuclear export signal (NES) is the small, hydrophobic, leucine-rich
NES, which was identified initially in the HIV-1 Rev protein and the cellular
kinase PKI (Fischer et al. 1995; Wen et al. 1995). Functionally related export
sequences resembling a leucine-rich NES have been detected since then in many
cellular and viral proteins of diverse functions with the capacity to shuttle between
the nucleus and the cytoplasm (La Cour et al. 2003). The direct interaction with
the importin-β-related export factor CRM1 (exportin1) is essential for the export
of proteins containing a leucine-rich NES (Fornerod et al. 1997) (Fig. 1). This
interaction can be inhibited specifically by the antibiotic leptomycin B (LMB),
resulting in a block of the nuclear export of proteins with a leucine-rich NES
(Kudo et al. 1999). CRM1 binds cooperatively to RanGTP and its export cargo,
leading to the formation of a trimeric transport complex in the nucleus. After
translocation of this complex through the NPC, the cytoplasmic RanGTP-binding
protein RanBP1 in concert with RanGAP dissociates the export complex (for a
review see Hutten and Kehlenbach 2007).
Nuclear RNA Export
The identification of CRM1 as a protein export factor was initiated by the finding
that nuclear export of unspliced HIV-1 RNA depends on binding of the viral pro-
tein Rev to CRM1 via a leucine-rich NES (Neville et al. 1997) (Fig. 2). Further
studies demonstrated that although CRM1 mediates nuclear export of HIV-1
mRNA, it is not responsible for the export of bulk cellular mRNA (Cullen 2003).
Instead, CRM1 acts as a RNA-export receptor for the export of rRNA, Usn RNAs
and several specific mRNAs (e.g., c-Fos, Cyclin D1, CD83), which is, however,
mediated via RNA-binding adapter proteins that interact with CRM1 (reviewed in
Hutten and Kehlenbach 2007) (Fig. 2).
In contrast to complex lentiviruses like HIV-1 encoding Rev-type RNA-binding
proteins, incompletely or unspliced RNAs from type D retroviruses are exported due
to the presence of a
cis
-acting RNA sequence named constitutive transport element
(CTE) (Bray et al. 1994). Investigation of the CTE-mediated export mechanism
allowed for the discovery of the major mRNA export receptor, named TAP/NXF1
(in yeast termed Mex67p), which interacts with the CTE element and thus facilitates
nuclear export of CTE-containing transcripts (Kang and Cullen 1999) (Fig. 2). Later
on, it was demonstrated that TAP interacts with p15, and that this heterodimer is
responsible for bulk metazoan mRNA export to the cytoplasm via direct interaction
with the nuclear pore (Katahira et al. 1999, 2002). Although TAP is able to bind
directly to CTE-containing viral mRNA, additional factors are needed to bridge the
interaction between TAP-p15 and metazoan mRNA since metazoan RNA does not
contain CTE-like RNA secondary structures (Liker et al. 2000). The production of
mature mRNA in eukaryotes involves a complex series of nuclear processing reac-
tions that occur co-transcriptionally and include the addition of the 5′ cap, removal
