The Neural F-Box Protein NFB42 Mediates the Nuclear Export of the Herpes Simplex Virus Type 1 Replication Initiator Protein (UL9 Protein) after Viral Infection

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-03, Vol.101 (12), p.4036-4040
• Main Authors: Eom, Chi-Yong, Heo, Won Do, Craske, Madeleine L., Meyer, Tobias, Lehman, I. Robert
• Format: Article
• Language: English
• Subjects: Biochemistry; Biological Sciences; Cell culture techniques; Cell Cycle Proteins - metabolism; Cell nucleus; Cell Nucleus - metabolism; Cytosol; Cytosol - metabolism; DNA-Binding Proteins - metabolism; F-Box Proteins; Gene expression; Herpes Simplex - metabolism; Herpes simplex virus 1; Herpes viruses; Herpesvirus 1, Human - metabolism; Hippocampus - metabolism; Human herpesvirus 1; Humans; Infections; Nerve Tissue Proteins - metabolism; Neurons; Neurons - metabolism; Protein Structure, Tertiary; Protein transport; Proteins; Transfection; Ubiquitins; Viral Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0400738101

The neural F-box 42-kDa protein (NFB42) is a component of the SCFNFB42E3 ubiquitin ligase that is expressed in all major areas of the brain; it is not detected in nonneuronal tissues. We previously identified NFB42 as a binding partner for the herpes simplex virus 1 (HSV-1) UL9 protein, the viral replication-initiator, and showed that coexpression of NFB42 and UL9 in human embryonic kidney (293T) cells led to a significant decrease in the level of UL9 protein. We have now found that HSV-1 infection promotes the shuttling of NFB42 between the cytosol and the nucleus in both 293T cells and primary hippocampal neurons, permitting NFB42 to bind to the phosphorylated UL9 protein, which is localized in the nucleus. This interaction mediates the export of the UL9 protein from the nucleus to the cytosol, leading to its ubiquitination and degradation via the 26S proteasome. Because the intranuclear localization of the UL9 protein, along with other viral and cellular factors, is an essential step in viral DNA replication, degradation of the UL9 protein in neurons by means of nuclear export through its specific interaction with NFB42 may prevent active replication and promote neuronal latency of HSV-1.