Biology Reference
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described as a multifunctional cellular protein: in addition to its role in recruiting
Aly/REF to mature mRNAs, it plays a well-documented role in pre-mRNA splic-
ing, where it facilitates the association of U2 snRNP with the splice branch point,
presumably by dissociating U2AF65 from the polypyrimdine track downstream of
the splice branchpoint (Fleckner et al. 1997). Furthermore, several studies propose
that the UAP56/BAT1 gene, which is situated in the central region of the major
histocompatibility complex, acts as an anti-inflammatory gene, and polymorphism
in its promoter region may predispose for specific inflammatory disorders (Allcock
et al. 1999, 2001; Ramasawmy et al. 2006). However, it is presently unclear
whether this potential antiinflammatory activity of UAP56 is related to its function
in mRNA processing and export.
RNA Export by pUL69
The detection of an interaction with URH49 and UAP56 suggested that pUL69,
similar to its counterparts in α- and γ-herpesviruses, may modulate nuclear mRNA
export. Taking advantage of a widely used functional reporter assay harboring the
CAT coding sequence and the Rev responsive element (RRE) of HIVI inserted into
an intron (Hope et al. 1990), both on the level of reporter protein and reporter RNA
expression, we showed that pUL69 facilitates the nuclear export of otherwise inef-
ficiently exported, unspliced RNA similar to Rev (Lischka et al. 2006b).
Furthermore, we were able to identify a 12-amino-acid sequence motif within the
N-terminus of pUL69, which turned out to be crucial for binding to UAP56
(Fig. 3): mutations within this motif abrogated both UAP56 binding and pUL69-
mediated nuclear export of unspliced RNA. This indicates that the interaction with
UAP56 or URH49 is required for pUL69 to promote cytoplasmic accumulation of
unspliced RNA (Lischka et al. 2006b).
However, in contrast to the HIV1 Rev protein, which interacts in a sequence-
specific manner with the viral RRE target sequence, this
cis
-acting element was
not necessary for pUL69 to facilitate RNA export. Presently, it is unclear whether
pUL69 requires a specific
cis
-acting RNA sequence to target viral RNAs for
export. Similar to ICP27, pUL69 is able to interact directly with RNA. This is
mediated via a complex N-terminal RNA-binding domain consisting of three
arginine-rich motifs that overlaps with both the NLS- and the UAP56-binding
motif (Fig. 3) (Toth et al. 2006). Surprisingly, however, an RNA-binding-
deficient mutant of pUL69, which still interacts with UAP56/URH49, retained its
RNA export activity. This suggests that in contrast to its homologs in other her-
pesviruses, RNA binding is not a prerequisite for pUL69-mediated nuclear RNA
export (Toth et al. 2006).
Another surprising finding was that the previously described nuclear export
sequence (NES) within pUL69 was clearly distinct from the UAP56 binding motif
(Fig. 3) (Lischka et al. 2001, 2006b). Nucleocytoplasmic shuttling is a feature that
