Varicella-zoster virus open reading frame 4 encodes an immediate-early protein with posttranscriptional regulatory properties

Abstract

Varicella-zoster virus (VZV) encodes four putative immediate-early proteins based on sequence homology with herpes simplex virus type 1: the products of ORF4, -61, -62, and -63. Until now, only two VZV proteins have been described as being truly expressed with immediate-early kinetics (IE62 and IE63). The ORF4-encoded protein can stimulate gene expression either alone or in synergy with the major regulatory protein IE62. Making use of a sequential combination of transcription and protein synthesis inhibitors (actinomycin D and cycloheximide, respectively), we demonstrated the immediate-early nature of the ORF4 gene product, which can thus be named IE4. The fact that IE4 is expressed with kinetics similar to that of IE62 further underlines the possible cooperation between these two VZV proteins in gene expression. Analysis of the IE4-mediated autologous or heterologous viral gene expression at the mRNA levels clearly indicated that IE4 may have several mechanisms of action. Activation of the two VZV genes tested could occur partly by a posttranscriptional mechanism, since increases in chloramphenicol acetyltransferase (CAT) mRNA levels do not account for the stimulation of CAT activity. On the other hand, stimulation of the human immunodeficiency virus type 1 long terminal repeat-or the cytomegalovirus promoter-associated CAT activity is correlated with an increase in the corresponding CAT mRNA.

Human Cytomegalovirus UL69 Protein Induces Cells To Accumulate in G 1 Phase of the Cell Cycle

“…Sequence homologues of UL69 and ICP27 have been identified in other members of the herpesvirus family, including ORF4 of varicella-zoster virus (20), UL3 of equine herpesvirus 1 (42), BMLF1 of Epstein-Barr virus (11,12), and IE52k of herpesvirus saimiri (1,32). ICP27 (31,35,41), UL69 (3,36,44), and several other members of this protein family (BMLF1 [24] and ORF4 [15,16]) have been shown to be transcriptional regulatory proteins. Perhaps they will prove to share cell cycle regulatory functions as well.…”

ORF61 protein of Varicella-zoster virus influences JNK/SAPK and p38/MAPK phosphorylation

“…Five of those, ORFs 4, 10, 61, 62, and 63, encode proteins with transregulatory activities. ORF 62 [Forghani et al, 1990], ORF 63 [Debrus et al, 1995], and ORF 4 [Defechereux et al, 1997] are expressed as IE proteins. The kinetic classes of ORF10 and ORF61 are not defined yet.…”

The human herpesvirus-8 ORF 57 gene and its properties

“…The presence of a homologue in every herpesvirus of mammals and birds sequenced so far suggests that aspects of the regulatory role of IE63 are maintained throughout the herpesvirus family. These homologues include EBV BMLF1, which has been shown to act post-transcriptionally, affecting RNA splicing and transport (Buisson et al , 1999 ), UL69 of human cytomegalovirus (HCMV; Winkler et al , 1994 ) and gene 4 of varicella-zoster virus (Defechereux et al , 1997 ). Studies of IE63 have highlighted the multifunctional nature of this protein, which acts at both transcriptional and post-transcriptional levels.…”