Mutations in host cell factor 1 separate its role in cell proliferation from recruitment of VP16 and LZIP

Host cell factor 1 (HCF-1) is a nuclear protein required for progression th rough G(1) phase of the cell cycle and, via its association with VP16, tran scriptional activation of the herpes simplex virus immediate-early genes. B oth functions require a six-bladed beta-propeller domain encoded by residue s 1 to 380 of HCF-1 as well as an additional amino-terminal region. The bet a-propeller domain is well conserved in HCF homologues, consistent with a c ritical cellular function. To date, the only known cellular target of the b eta-propeller is a bZIP transcription factor known as LZIP or Luman. Whethe r the interaction between HCF-1 and LZIP is required for cell proliferation remains to be determined. In this study, we used directed mutations to sho w that all six blades of the HCF-1 beta-propeller contribute to VP16-induce d complex assembly, association with LZIP, and cell cycle progression. Alth ough LZIP and VP16 share a common tetrapeptide HCF-binding motif, our resul ts reveal profound differences in their interaction with HCF-1. Importantly , with several of the mutants we observe a poor correlation between the abi lity to associate with LZIP and promote cell proliferation in the context o f the full HCF-1 amino terminus, arguing that the HCF-1 beta-propeller doma in must target other cellular transcription factors in order to contribute to G(1) progression.