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property of all members of this protein family, namely the propensity to self- interact
and thus to form multimeric protein complexes (Lischka et al. 2007).
A second shared feature of all characterized members of this protein family is
a function as posttranscriptional regulators. For instance, the prototype of this
protein family, ICP27 of HSVI, has been shown to redistribute small nuclear
ribonucleoprotein particles (snRNPs), to inhibit cellular splicing, to bind to
intronless viral RNAs, and to shuttle between the nucleus and the cytoplasm, thus
acting as a viral mRNA export factor (reviewed by Sandri-Goldin 2004; Sandri-
Goldin 2001; Smith et al. 2005). The latter properties are of particular importance
for herpesviruses since the majority of viral transcripts are intronless and thus do
not interact with the splicing machinery, leading to inefficient nuclear export of
viral mRNA. Further investigation of the RNA export mechanism revealed that
ICP27 binds viral RNA through an N-terminal RGG box RNA-binding motif
(Mears and Rice 1996; Sandri-Goldin 1998). Additionally, ICP27 was shown to
interact with the adaptor protein Aly/REF, thereby recruiting intronless viral
RNAs to the cellular TAP-p15 mRNA export receptor (Chen et al. 2002; Koffa
et al. 2001) (see Fig. 4). An interaction with Aly/REF could also be demonstrated
for the γ-herpesviral proteins EB2 of EBV and ORF 57 of KSHV or HVS, sug-
gesting that several ICP27 homologous proteins may use a common mechanism
for the nuclear export of viral intronless mRNAs (Hiriart et al. 2003; Malik et al.
2004; Williams et al. 2005).
Initial studies on the HCMV homolog of ICP27, the UL69 protein, revealed
several differences between these two regulatory factors:
1. In contrast to the immediate early expression of ICP27, pUL69 could be
detected during the early and late phase of the replication cycle and is incorpo-
rated as a tegument protein into viral particles (Winkler et al. 1994; Winkler
and Stamminger 1996);
2. pUL69 did not repress expression depending on the presence of an intron within
a reporter gene but revealed a rather pleiotropic activation of various promoters
upstream of the luciferase reporter (Sandri-Goldin and Mendoza 1992; Winkler
et al. 1994);
3. No redistribution of snRNPs is induced by pUL69 (Winkler et al. 2000);
4. pUL69 could not complement the growth of an ICP27 deletion mutant of
HSVI, further emphasizing the existence of functional differences (Winkler
et al. 1994).
In an attempt to unravel the mechanism of pUL69-mediated transactivation, we
searched for cellular interaction partners of this viral protein by yeast two hybrid
screenings, which revealed at least two proteins with a potential role for mRNA
biogenesis and processing. One of the identified cellular proteins corresponded to
the transcription elongation factor hSPT6 (Endoh et al. 2004; Kaplan et al. 2000);
we were able to demonstrate that this interaction occurs within the conserved
homology region of pUL69 and is functionally required for pUL69-mediated trans-
activation (Winkler et al. 2000). Interestingly, hSpt6 has recently been shown to
bind both to the C-terminal domain of RNA polymerase II and to a novel factor
