Adam P. Geballe

Translational regulation of viral and cellular gene expression

Studies in an increasing number of systems demonstrate that translational events have a major impact on eukaryotic gene expression. Research in the Geballe lab aims to identify the cis-acting signals and trans-acting factors and to elucidate the mechanisms that regulate expression of viral and cellular genes at the translational level. As well the lab has begun investigating the evolution of mechanism sby which viruses overcome host cell defenses, several of which act by inhibiting translation in the infected cell.

Human cytomegalovirus (HCMV), a member of the herpesvirus family, typically produces few if any symptoms in otherwise healthy individuals, but often causes life-threatening infections in newborns, solid organ and hematopoietic stem cell transplant recipients, and other immunocompromised patients. In addition to its medical importance, HCMV is also a useful model system for the study of translational regulation of eukaryotic gene expression. Host cells respond to viral infections by activating several antiviral pathways, including ones that are triggered by interferons and activated by double-stranded RNA (dsRNA), and that act by shutting off protein synthesis. To enable the continued protein synthesis that is necessary for replication, many viruses including HCMV have evolved means of inactivating these pathways. A genetic screen identified two HCMV genes that participate in maintaining translational capacity in the infected cell despite activation of these host responses. These genes bind to dsRNA through an unconventional dsRNA binding domain and a PKR binding domain, both of which are necessary for blocking the antiviral pathways. The proteins also self-associate and cause PKR relocalization to the nucleus, an unusual effect among viral anti-PKR protein. On-going studies of related viruses, including other CMVs, are illuminating adaptations that have occurred during the evolutionary "arms race" between PKR and its viral antagonists and are proving valuable in elucidating the critical components of the mechanism. Current efforts aim to elucidate the activities of the various domains of these genes and to identify other viral and cellular factors needed to maintain the robust protein synthetic capacity in CMV-infected cells.

The lab is also collaborating with the Malik lab to investigate how poxviruses overcome host cell defenses. Comparisons of the solutions that poxviruses and herpesvirus have evolved to overcome the myriad the antiviral pathways is providing new insights into conserved as well as viral-specific mechanism that enable successful replication of large DNA viruses.