The interaction between Brn-3a POU proteins with LIM-1 proteins and their role on HSV genome

Abstract

The repeated recurrence of epithelial lesions following initial infection with Herpes Simplex Virus (HSV) is dependent upon the establishment of asymptomatic latent infections of sensory neurons from which the virus can repeatedly emerge to attack susceptible epithelial cells. The failure of the viral lytic cycle and consequent establishment of latent infections in sensory neurons is due to a lack of viral immediate-early (IE) gene expression following initial infection. The lytic infection of the viral genome is expressed in three stages, resulting in the sequential transcription of the immediate-early, early and late genes. The temporal regulation of HSV-1 gene expression during permissive infection commences with the induction of the immediate- early genes (IE) by the virion protein VP16. VP16 activates transcription by binding, along with the cellular factors Oct-1 and host cell factor (HCF), to the TAATGARAT (R=purine) elements present in all IE promoters. IE1 (ICP4) is the major regulatory protein of the virus, and it is necessary for the transition of viral gene transcription from the IE to the early (E) phase. IE3 (ICPO) is a potent trans-activator of viral and cellular promoters in transient assays, and it provides for efficient viral gene expression and growth, in vitro and in vivo. Regarding Oct-2, the single RNA transcript produced from the Oct-2 gene is subject to alternative splicing to produce different forms of the mRNA in B-lymphocytes compared to neuronal cells. The predominantly B cell form Oct-2.1 has a stimulatory effect on gene expression, while the predominant neuronal forms Oct-2,4 and Oct-2.5 have an inhibitory effect on gene expression by repressing promoters such as those of the HSV immediate early genes and the cellular tyrosine hydroxylase gene. Another family of POU proteins -Brn-3- has also revealed to play a critical role in IE gene expression. Brn-3 family of transcription factors, are the most closely related to the unc-86 within the POU domain. Following the identification of the founder members of the Brn-3 family, known as Brn-3a, two other members of the family have been identified and they are known as Brn-3b and Brn-3c and are expressed at high levels in sensory neurons. The three different Brn-3 factors are encoded by three distinct genes and show only restricted homology to one another outside the POU domain. Those transcription factors have also been shown to bind to several octamer/TAATGARAT-related sequences and to modulate the activity of artificial test promoters containing such proteins. LIM-HD proteins are a major class of transcriptional activators that cooperate with other activators to direct cellular differentiation. LIM-HD proteins contain a DNA binding homeodomain and two N-terminal zinc-binding LIM domains. Lim-1 is a LIM-HD protein. In previous studies it has been shown that LIM-HD proteins exhibit transcriptional synergy when they interact with basic helix-loop-helix proteins. In our studies we investigated the role between the Lim-1 protein and Brn-3a/Brn-3c proteins in the IE gene expression of HSV-1. It was demonstrated that LIM-HD proteins are expressed in SNS and expression is regulated by NGF. Brn-3a, Brn-3c in conjunction with Lim-1 synergise, in the induction of ICPO expression. It was also shown that lsl-1 and Brn-3 proteins interact synergistically and induce ICPO gene expression. Similar experiments in ICP4 gene expression revealed no induction in gene expression It was also evident that the induction of the ICPO expression happens via the octamer/TAATGARAT motif when ND7 and BHK cell lines were used. Furthermore, we demonstrated the roles of the two domains of Lim-1 in this interaction with Brn-3 proteins. Results from deletion mutations revealed that both domains of Lim-1 are required for the synergism to happen.

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