Abstract
HCF-1 is a cellular protein required by VP16 to activate the herpes simplex virus (HSV) immediate-early genes. VP16 is a component of the viral tegument and, after release into the cell, binds to HCF-1 and translocates to the nucleus to form a complex with the POU domain protein Oct-1 and a VP16-responsive DNA sequence. This VP16-induced complex boosts transcription of the viral immediate-early genes and initiates lytic replication. In uninfected cells, HCF-1 functions as a coactivator for the cellular transcription factors LZIP and GABP and also plays an essential role in cell proliferation. VP16 and LZIP share a tetrapeptide HCF-binding motif recognized by the beta-propeller domain of HCF-1. Here we describe a new cellular HCF-1 beta-propeller domain binding protein, termed HPIP, which contains a functional HCF-binding motif and a leucine-rich nuclear export sequence. We show that HPIP shuttles between the nucleus and cytoplasm in a CRM1-dependent manner and that overexpression of HPIP leads to accumulation of HCF-1 in the cytoplasm. These data suggest that HPIP regulates HCF-1 activity by modulating its subcellular localization. Furthermore, HPIP-mediated export may provide the pool of cytoplasmic HCF-1 required for import of virion-derived VP16 into the nucleus.
Highlights
Lytic replication in herpes simplex virus begins with the expression of the five viral immediate-early (IE)1 genes that encode multifunctional regulatory proteins necessary for expression of the early genes and creation of an optimal environment for viral replication
We show that HPIP shuttles between the nucleus and cytoplasm in a CRM1-dependent manner and that overexpression of HPIP leads to accumulation of HCF-1 in the cytoplasm
The HCF-1 polypeptide is synthesized as a 2035amino acid precursor that is subsequently processed into two subunits through proteolytic cleavage at six HCFPRO repeats located near the center of the precursor (18 –21)
Summary
Lytic replication in herpes simplex virus begins with the expression of the five viral immediate-early (IE)1 genes that encode multifunctional regulatory proteins necessary for expression of the early genes and creation of an optimal environment for viral replication (reviewed in Ref. 1). We describe a new cellular HCF-1 -propeller domain binding protein, termed HPIP, which contains a functional HCF-binding motif and a leucine-rich nuclear export sequence. B, 293T cells were cotransfected with expression plasmids encoding wild type or mutant versions of GFP-HPIP (3 g) and HA-tagged HCF-1N380 (2 g).
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