Potential role for luman, the cellular homologue of herpes simplex virus VP16 (alpha gene trans-inducing factor), in herpesvirus latency

The cascade of herpes simplex virus (HSV) gene expression that results in v iral replication begins with the activation of viral immediate-early (IE) g enes by the virion-associated protein VP16. VP16 on its own is inefficient at associating with complexes formed on IE gene promoters and depends upon the cellular factor HCF for its activity. In this respect VP16 mimics the h ost basic leucine zipper (bZIP) protein Luman, which also requires HCF for activating transcription. Our objective is to explore interactions between Lumen and HCF and to determine if they play a role in the biology of herpes viruses. In this report we show that in cultured cells ectopically expresse d Luman was retained in the cytoplasm, where it colocalized with Calnexin, a protein normally associated with the endoplasmic reticulum (ER). Retentio n of Luman in the ER depends on a hydrophobic segment of the protein that p robably serves as a transmembrane domain. Deletion of this domain changed t he intracellular location of Luman so that most of the mutant protein was i n the nucleus of cells. While HCF was present in the nucleus of most cells, in cells expressing Luman it was retained in the cytoplasm where the two p roteins colocalized, This cytoplasmic association of Luman and HCF could al so be demonstrated in neurons in trigeminal ganglia removed from cattle soo n after death. Cells in tissue culture that expressed Luman, but not a muta nt form of the protein that fails to bind HCF, were resistant to a producti ve infection with HSV type 1 (HSV-1). We hypothesize that similar Luman-HCF interactions in sensory neurons in trigeminal ganglia result in the suppre ssion of viral replication and the establishment of latency. Interestingly, Luman could activate the promoters of IE110 and LAT, two genes that are cr itical for reactivation of HSV-1 from latency. This suggests a role for Lum an in the reactivation process as well.