Abstract

HCF-1, the metazoan host cell factor-1 is a conserved cellular transcription factor also called VCAF1, C1, or CCF. This protein became of interest as an accessory protein required for the lytic mode of herpes simplex virus infection in association with the virion protein VP16 (reviewed by Wysocka and Herr, 2003; Kristie et al. 2010). HCF-1 is exclusively nuclear and expressed in almost all mammalian cell types (Ajuh et al., 2002). The homologues of HCF-1 are present both in vertebrates and invertebrates but with sufficient divergence that the lineages may have somewhat different functions. The association of HCF-1 with several transcription factors showed the possible role for the protein in gene transcription (Lu et al., 1997, 1998; Lu and Misra, 2000). In addition HCF-1 may play an important role in spliceosome assembly and pre-mRNA splicing in mammals (Ajuh et al., 2002), cell proliferation (Freiman and Herr, 1997; Dutta et al., 2009) and cell cycle progression (Wysocka et al., 2001). Interactions with several E2F factors are strong indications of the importance of HCF-1 for cell cycle regulation (Tyagi et al., 2007).

The human HCF-1 polypeptide is synthesized as a large precursor that is subsequently cleaved at specific repeats located towards the centre of the protein that are specific targets of proteolysis. After cleavage the resulting family of polypeptides remain bound together through the action of two pairs of self association sequences, SAS1 and SAS2 ( Wilson et al., 2000). HCF-1 possesses several distinct polypeptide regions. The N-terminal region contains a Kelch domain consisting of six Kelch repeats, which are predicted to form a beta-propeller structure of linked beta sheets. The C-terminal region of HCF-1 encompasses two Fibronectin type III repeats. A classical bipartite nuclear localization signal (NLS), which is necessary for the nuclear localization of the protein, is located at the extreme C-terminus, just downstream of the FnIII repeats. HCF-1N is essential for G1 phase progression, whereas HCF-1C is important for proper cytokinesis. A number of transcriptional regulatory proteins contain a [DE]HxY motif designated the HCF-1 binding motif (HBM). The HBM interacts with the kelch domain, aiding recruitment of HCF-1 to the promoters it regulates. HBM-containing proteins include transcription factors such as E2Fs, Krox20, CREB3 as well as histone methyltransferases such as MLL and SET1A. The HCV transcriptional regulatory protein VP16 also contains the HBM motif and such usage may be more widespread for viral hijack of the cell cycle.