The Neuronal Host Cell Factor-Binding Protein Zhangfei Inhibits Herpes Simplex Virus Replication

Abstract

During lytic infection in epithelial cells the expression of herpes simplex virus type 1 (HSV-1) immediateearly (IE) genes is initiated by a multiprotein complex comprising the virion-associated protein VP16 and two cellular proteins, host cellular factor (HCF) and Oct-1. Oct-1 directly recognizes TAATGARAT elements in promoters of IE genes. The role of HCF is not clear. HSV-1 also infects sensory neurons innervating the site of productive infection and establishes a latent infection in these cells. It is likely that some VP16 is retained by the HSV-1 nucleocapsid as it reaches the neuronal nucleus. Its activity must therefore be suppressed for successful establishment of viral latency. Recently, we discovered an HCF-binding cellular protein called Zhangfei. Zhangfei, in an HCF-dependent manner, inhibits Luman/LZIP/CREB3, another cellular HCFbinding transcription factor. Here we show that Zhangfei is selectively expressed in human neurons. When delivered to cultured cells that do not normally express the protein, Zhangfei inhibited the ability of VP16 to activate HSV-1 IE expression. The inhibition was specific for HCF-dependent transcriptional activation by VP16, since a Gal4-VP16 chimeric protein was inhibited only on a TAATGARAT-containing promoter and not a on a Gal4-containing promoter. Zhangfei associated with VP16 and inhibited formation of the VP16-HCFOct-1 complex on TAATGARAT motifs. Zhangfei also suppressed HSV-1-induced expression of several cellular genes including topoisomerase II␣, suggesting that in addition to suppressing IE expression Zhangfei may have an inhibitory effect on HSV-1 DNA replication and late gene expression.Herpes simplex virus type 1 (HSV-1) uses two complementary strategies to avoid immune surveillance and to maintain itself in its host. Infection begins with virus replication and the lysis of infected epithelial cells. During this phase of lytic replication the virus infects sensory nerves and establishes a latent infection in neuronal nuclei located in sensory ganglia (reviewed in reference 6). The virus is thought to be almost completely quiescent during latent infection. Only one viral transcript and no readily detectible viral proteins are expressed. A variety of physiological and psychological stressors reactivate the latent viral genome to reenter the lytic phase. Following reactivation, the virus replicates in neurons and travels down the axons of sensory neurons to replicate again in epithelial cells causing a recrudescent lesion (reviewed in references 37 and 38).During the lytic infection of epithelial cells the expression of viral genes is temporally regulated and the approximately 80 viral genes involved can be described as immediate-early (IE), early (E), or late (L) depending upon the order of their expression. Initiation of the transcription of the five IE genes (ICP0, ICP4, ICP22, ICP27, and ICP47) is induced by the assembly of a multiprotein complex (VP16-induced complex [VIC]) made up of the virion protein VP16 and the two cellular proteins Oct-1 and host cel...

Transcriptional Corepressor SMILE Recruits SIRT1 to Inhibit Nuclear Receptor Estrogen Receptor-related Receptor γ Transactivation

“…The bZIP protein SMILE has been reported to regulate the transactivation of several transcription factors, including ERs, host-cell factor, CREB3, and ATF4 (6,(17)(18)(19). Recently, we have reported that SMILE acts as a novel corepressor of nuclear receptors GR, CAR, and HNF4␣ (20).…”

“…However, SMILE cannot bind to DNA as homodimers, although it can homodimerize like other bZIP proteins (15,17). SMILE has been implicated in herpes simplex virus infection cycle and related cellular processes through its association with herpes simplex virus-related host-cell factor and CREB3 (17,18).…”

Effects of cyclic AMP response element binding protein–Zhangfei (CREBZF) on the unfolded protein response and cell growth are exerted through the tumor suppressor p53

“…While Zhangfei can activate gene expression through factors such as p53 2 and ATF4, 3 it suppresses the activity of a number of transcription factors, which includes nuclear receptors, [4][5][6] bLZip containing proteins such as CREBH, 7 Luman/CREB3, 8 Xbp1, and SMAD 1,5,8, 9 and the HCFbinding VP16. 10 Zhangfei also has a profoundly suppressive effect on the unfolded protein response (UPR), at least partly because it targets Xbp1s, an important UPR mediator, for proteasomal degradation. 11 We have detected Zhangfei protein in differentiated neurons, but not in developing neurons or cells of neuronal tumors, 10 nor in osteosarcoma cell lines.…”

“…10 Zhangfei also has a profoundly suppressive effect on the unfolded protein response (UPR), at least partly because it targets Xbp1s, an important UPR mediator, for proteasomal degradation. 11 We have detected Zhangfei protein in differentiated neurons, but not in developing neurons or cells of neuronal tumors, 10 nor in osteosarcoma cell lines. The ectopic expression of Zhangfei in several tumor cells lines derived from medulloblastomas (ONS-76, UW228 12 ) and osteosarcomas (D-17 13 ) causes the cells to stop growing and display markers of apoptosis.…”

Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis

“…Small heterodimer partner-interacting leucine zipper protein (SMILE), including two alternative translation-derived isoforms, SMILE-L (CREBZF: long form of SMILE) and SMILE-S (Zhangfei: short form of SMILE), has been classified as a member of the CREB/ATF family of basic regionleucine zipper transcription factors. However, SMILE cannot bind to DNA as a homodimer (10)(11)(12). SMILE has also been reported to function as a coactivator of activating transcription factor 4 or as a corepressor of host cell factor-binding transcription factor (13,14).…”