This new project headed by Dr. DiMaio is based on a discovery made in project 2 during the current funding period. The polyomaviruses, BK virus andJC virus, cause serious diseases in immunosuppressed individuals including cancer patients and, like their close relative SV40, are putative human tumor viruses. With the support of this grant, we discovered that the cellular co-chaperones DNAJ-B12 and DNAJ-B14 are required for efficient infection by these three viruses. When expression of these genes is repressed by shRNAs, there is a substantial reduction in expression of the major early protein, large T antigen. Virus binding to the cell surface appears unimpaired, suggesting that the DNAJ-B12/14 sensitive step(s) is in some aspect of virus entry, intracellular trafficking, or uncoating. We will conduct a series of biochemical, cell biological and genetic studies to elucidate the mechanistic role played by DNAJ-B12/14 in SV40 infection. We will determine how far infection proceeds in cells lacking DNAJ-B12/14 function, and determine what step in the virus entry/trafficking/uncoating process is blocked. We will conduct mutational and biochemical analysis of DNAJ-B12/14 to determine its mode of action at the molecular level. Viral escape mutants that allow infection despite DNAJ-B12/14 repression will be isolated and characterized. Finally, we will use shRNA technology to determine whether other members of the DNAJ gene family are required for infection by the polyomaviruses and other viruses, including Epstein-Barr virus in collaboration with Dr. Miller. These experiments will provide new insights into the process of tumor virus infection and characterize the role of new putative anti-viral targets.
The polyomaviruses cause serious disease in humans and are putative human tumor viruses. We have discovered two cellular genes that are required for infection by these viruses, and we will determine how their protein products facilitate infection. These experiments will provide new insight into infection by pathogenic human viruses and may lead to new approaches to treat or prevent the diseases they cause.
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|Goodwin, Edward C; Motamedi, Nasim; Lipovsky, Alex et al. (2014) Expression of DNAJB12 or DNAJB14 causes coordinate invasion of the nucleus by membranes associated with a novel nuclear pore structure. PLoS One 9:e94322|
|Cech, Thomas R; Steitz, Joan A (2014) The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157:77-94|
|Dimaio, Daniel (2014) Is virology dead? MBio 5:e01003-14|
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|Carney, Daniel W; Nelson, Christian D S; Ferris, Bennett D et al. (2014) Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses. Bioorg Med Chem 22:4836-47|
|Zhang, Wei; Kazakov, Teymur; Popa, Andreea et al. (2014) Vesicular trafficking of incoming human papillomavirus 16 to the Golgi apparatus and endoplasmic reticulum requires ?-secretase activity. MBio 5:e01777-14|
|Xie, Mingyi; Steitz, Joan A (2014) Versatile microRNA biogenesis in animals and their viruses. RNA Biol 11:673-81|
|Park, Richard; El-Guindy, Ayman; Heston, Lee et al. (2014) Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. PLoS One 9:e92593|
|Guo, Yang Eric; Steitz, Joan A (2014) Virus meets host microRNA: the destroyer, the booster, the hijacker. Mol Cell Biol 34:3780-7|
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