Abstract
Host cell factor (HCF) was initially discovered as a cellular co-factor required for the activation of herpes simplex virus immediate early gene expression by the virion associated transactivator VP16. HCF also participates in a variety of cellular processes, although the mechanism of its action is not known. VP16 binds to HCF through a 4-amino acid motif (EHAY), which closely resembles the HCF binding domain of two cellular basic leucine-zipper proteins, Luman and Zhangfei. Luman is a powerful transcription factor that, in transient expression assays, activates promoters containing cAMP or unfolded protein response elements (UPRE). In contrast, Zhangfei neither binds consensus recognition elements for basic leucine-zipper proteins nor does it activate promoters containing them. Here we show that Zhangfei suppresses the ability of Luman to activate transcription. HCF appeared to be required for efficient suppression. A mutant of Zhangfei, which was unable to bind HCF, was impaired in its ability to suppress Luman. Zhangfei did not suppress ATF6, a transcription factor closely related to Luman but that does not bind HCF, unless the HCF binding motif of Luman was grafted onto it. Zhangfei inhibited the HCF-dependent activation of a UPRE-containing promoter by a Gal4-Luman fusion protein but was unable to inhibit the HCF-independent activation by Gal4-Luman of a promoter that contained Gal4 binding motifs. Binding of HCF by Zhangfei was required for the co-localization of Luman and Zhangfei to nuclear domains, suggesting that HCF might target the proteins to a common location.
Highlights
Host cell factor (HCF)1 is an abundant and ubiquitous chromatin-associated protein
Host Cell Factor has been implicated in many cellular and viral processes, and at least some of these appear to be mediated through direct interaction between HCF and HCF binding motif (HBM) present in several transcription factors
For those factors such as VP16, Luman, Krox20, and E2F4, where the interaction has been examined in any detail, HCF binding appears to be required for the activity of the factors
Summary
Host cell factor (HCF) is an abundant and ubiquitous chromatin-associated protein. It was initially discovered as a component of a multiprotein complex assembled with the herpes simplex virus (HSV) transactivator VP16 (reviewed in Ref. 1). The amino-terminal segment of the protein is believed to fold into a six-bladed propeller-like structure called the Kelch domain, because of its similarity to the Drosophila Kelch protein (reviewed in Ref. 1) This domain has features needed for interaction with VP16 as well as the cellular proteins Luman/L-ZIP/ CREB3 [10, 11], Zhangfei [12], HPIP, Set1/Ash2 [8, 13], and Krox and E2F4 [14]. Luman is a basic leucine-zipper (B-Zip) transcription factor that, in vitro, can bind cAMP and unfolded protein response elements (CRE and UPRE) Both proteins appear to be selectively expressed in neurons [18].2. Because of this, Zhangfei does not bind any of the consensus B-Zip response elements examined and cannot activate transcription from promoters that
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