Molecular Biology of Translational Control

Translational control of gene expression - Regulation of gene activity during early development -Host defense against virus infection and viral countermeasures - Role of protein synthesis in lactation.

Research interests

• function/evolution of eIF4E related proteins
• function of eIF4E family members in zebrafish development
• role of an interferon-induced protein kinase, PKR, in the molecular pathogenesis of fish viruses
• translational mechanisms governing milk protein production in mammary gland

Until recently, it was believed, through extrapolation from genetic studies in the yeast, that eIF4E was encoded by a single gene in higher eukaryotes. However, recently, through the analysis of whole genome sequences and ESTs, it has become apparent that genes producing many different eIF4E related proteins exist in higher eukaryotes. C. elegans expresses five eIF4E isoforms, Drosophila has six eIF4E genes. Based on sequence homologies and our knowledge of the 3-D structure of mouse/human eIF4E-1, three classes of eIF4E have been recognized by the Jagus laboratory; Class I (prototypical eIF4E and subtypes), Class II (eIF4ELP/HP), and Class III (eIF4E-3) which is found only in vertebrates. Classes II and III are divergent in one or more conserved tryptophans and in the eIF4G/4EBP binding site. A major goal of the Jagus laboratory is to elucidate their respective roles in the regulation of gene expression. We have found two additional eIF4Es in mammals, 4ELP/HP and eIF4E-3 and have also found five eIF4Es in zebrafish, three Class I and one representative each of Class II and Class III. As an outgrowth of the eIF4E family member project, currently funded through NSF, we have become interested in the role of 4ELP/HP in translational mechanisms governing milk protein production in mammary gland, an extremely understudied area of research.

--For the comparative analyses of eIF4E-family members, click here: eIF4E Database

As a separate thrust, we are working on host defense mechanisms in salmonids, about which little is known. We have found that the phosphorylation state of fish eIF2a increases in response to infection by the fish Aquabirnavirus, IPNV, and that the degree of phosphorylation correlates with the multiplicity of infection. The finding that eIF2a is phosphorylated in response to IPNV infection of RTG-2 cells implies that PKR is also present in fish. We have isolated an eIF2a-kinase from the RTG-2 rainbow trout cell line with characteristics indicating it is the interferon-induced dsRNA-activated protein kinase PKR (rtPKR). In fish cell lines, rtPKR is upregulated by interferon and activated by dsRNA and IPNV infection. These studies highlight the interferon/eIF2a/PKR response to virus infection as an ancient vertebrate protective mechanism. The tools developed have opened up avenues for the development of antiviral defense strategies, as well as the possibility of using PKR levels/activity as a means of assessing vaccine efficacy or brood stock resistance.