%0 Journal Article %1 10.1371/journal.ppat.1008030 %A Wang, Liang Wei %A Wang, Zhonghao %A Ersing, Ina %A Nobre, Luis %A Guo, Rui %A Jiang, Sizun %A Trudeau, Stephen %A Zhao, Bo %A Weekes, Michael P. %A Gewurz, Benjamin E. %D 2019 %I Public Library of Science %J PLOS Pathogens %K B-cell Epstein-Barr LMP1 LMP2A Rab metabolism mevalonate myown virus %N 9 %P 1-35 %R 10.1371/journal.ppat.1008030 %T Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival %U https://doi.org/10.1371/journal.ppat.1008030 %V 15 %X Author summary EBV, the first human tumor virus identified, persistently infects >95% of adults worldwide. Upon infection of small, resting B-lymphocytes, EBV establishes a state of viral latency, where viral oncoproteins and non-coding RNAs activate host pathways to promote rapid B-cell proliferation. EBV’s growth-transforming properties are closely linked to the pathogenesis of multiple immunoblastic lymphomas, particularly in immunosuppressed hosts. While EBV oncogenes important for B-cell transformation have been identified, knowledge remains incomplete of how these EBV factors remodel cellular metabolism, a hallmark of human cancers. Using a recently established proteomic map of EBV-mediated B-cell growth transformation, we found that EBV induces biosynthetic pathways that convert acetyl-coenzyme A (acetyl-CoA) into isoprenoids, steroids, terpenoids, cholesterol, and long-chain fatty acids. Viral nuclear antigens cooperated with EBV-activated host transcription factors to upregulate rate-limiting enzymes of these biosynthetic pathways. The isoprenoid geranylgeranyl pyrophosphate was identified as a key product of the EBV-induced mevalonate pathway. Our studies highlighted GGPP roles in Rab protein activation, and Rab13 was identified as a highly EBV-upregulated GTPase critical for LMP1 and LMP2A trafficking and signaling. These studies identify multiple EBV-induced metabolic enzymes important for B-cell transformation, including potential therapeutic targets.

@article{10.1371/journal.ppat.1008030, abstract = {Author summary EBV, the first human tumor virus identified, persistently infects >95% of adults worldwide. Upon infection of small, resting B-lymphocytes, EBV establishes a state of viral latency, where viral oncoproteins and non-coding RNAs activate host pathways to promote rapid B-cell proliferation. EBV’s growth-transforming properties are closely linked to the pathogenesis of multiple immunoblastic lymphomas, particularly in immunosuppressed hosts. While EBV oncogenes important for B-cell transformation have been identified, knowledge remains incomplete of how these EBV factors remodel cellular metabolism, a hallmark of human cancers. Using a recently established proteomic map of EBV-mediated B-cell growth transformation, we found that EBV induces biosynthetic pathways that convert acetyl-coenzyme A (acetyl-CoA) into isoprenoids, steroids, terpenoids, cholesterol, and long-chain fatty acids. Viral nuclear antigens cooperated with EBV-activated host transcription factors to upregulate rate-limiting enzymes of these biosynthetic pathways. The isoprenoid geranylgeranyl pyrophosphate was identified as a key product of the EBV-induced mevalonate pathway. Our studies highlighted GGPP roles in Rab protein activation, and Rab13 was identified as a highly EBV-upregulated GTPase critical for LMP1 and LMP2A trafficking and signaling. These studies identify multiple EBV-induced metabolic enzymes important for B-cell transformation, including potential therapeutic targets.}, added-at = {2019-09-21T18:32:29.000+0200}, author = {Wang, Liang Wei and Wang, Zhonghao and Ersing, Ina and Nobre, Luis and Guo, Rui and Jiang, Sizun and Trudeau, Stephen and Zhao, Bo and Weekes, Michael P. and Gewurz, Benjamin E.}, biburl = {https://www.bibsonomy.org/bibtex/22daa50e578ed6a57fb19b6c456cf5d67/bgewurz}, doi = {10.1371/journal.ppat.1008030}, interhash = {f8b78a21e853fb201286f6ca462d0fb0}, intrahash = {2daa50e578ed6a57fb19b6c456cf5d67}, journal = {PLOS Pathogens}, keywords = {B-cell Epstein-Barr LMP1 LMP2A Rab metabolism mevalonate myown virus}, month = {09}, number = 9, pages = {1-35}, publisher = {Public Library of Science}, timestamp = {2019-09-22T04:28:53.000+0200}, title = {Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival}, url = {https://doi.org/10.1371/journal.ppat.1008030}, volume = 15, year = 2019 }