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Bert L. Semler
Positions:
Professor, Microbiology & Molecular Genetics
School of Medicine

Director, Center for Virus Research
Research Centers and Institutes

picture of Bert L. Semler
Degrees:
B.S., University of California, Irvine, 1974
Ph.D., University of California, San Diego, 1979
Academic
Distinctions
American Cancer Society Postdoctoral Fellowship; NIH National Research Service Award; American Cancer Society Faculty Research Award; NIH Research Career Development Award; Athalie Clark Outstanding Research Award-UCI College of Medicine; ISI Highly Cited Researcher; Elected, Fellow of the American Academy of Microbiology; Senior Fellow of the American Asthma Foundation; Elected, Fellow of the American Association for the Advancement of Science (AAAS); Elected, President of the American Society for Virology
   
Research
Interests:
RNA virus gene expression; RNA-protein and protein-protein interactions; mechanisms of replication of picornavirus genomic RNAs; mechanisms of translation initiation for viral and cellular mRNAs
Research
Abstract:
Our research focuses on how picornaviruses (including human rhinovirus, poliovirus, and coxsackievirus) regulate the expression and replication of their genomic RNAs in infected human cells. The limited coding capacity of picornavirus genomic RNAs results in a genetically-challenged RNA virus. As a result, picornaviruses have evolved to utilize host cell proteins in different steps of their intracellular, cytoplasmic replication cycles. Somewhat surprisingly, several proteins known or suspected to have roles in viral gene expression and RNA replication reside primarily in the nucleus of uninfected mammalian cells. Due to viral-specific alteration of protein trafficking between the cytoplasm and the nucleus of infected cells, such proteins become available for viral functions in the cytoplasm. We have identified two HeLa cell proteins that fall into this unusual category of nuclear proteins involved in the cytoplasmic functions of poliovirus. The first of these proteins is SRp20, a member of a group of pre-mRNA splicing factors known to act at several steps during constitutive eukaryotic mRNA splicing. SRp20 has also been implicated in the export of mRNAs from the nucleus to the cytoplasm. Using in vitro translation assays as well as RNA interference experiments in HeLa cells, we demonstrated that SRp20 is required for poliovirus translation initiation. We have used confocal microscopy to show that within 3 hr post-infection, SRp20 begins to re-localize from the nucleus to the cytoplasm in poliovirus-infected neuroblastoma cells. Some of this cytoplasmic SRp20 co-localizes with another host cell RNA binding protein (PCBP2) that is involved in poliovirus IRES-mediated translation initiation. We generated an SRp20 deletion construct (SRp20deltaRRM) that lacks the RNA-recognition motif but still contains the domain required for interaction with PCBP2 (the RS domain). We found that the localization of this mutated protein is similar to wild type SRp20 in mock- or poliovirus-infected cells, and SRp20deltaRRM also partially co-localizes with PCBP2 in infected cells at 3 hr post-infection. In addition, we showed that expression of SRp20deltaRRM results in an approximate two-log defect in poliovirus growth, suggesting that the deleted protein acts as a dominant negative factor in poliovirus translation. A second predominantly nuclear protein that re-localizes to the cytoplasm of cells infected with poliovirus is hnRNP C, a highly abundant protein in human cells that functions in cellular mRNA biogenesis processes in the nucleus, including mRNA splicing and stabilization of pre-mRNA. We found that hnRNP C binds to both the 5’ and 3’ ends of poliovirus negative-strand RNAs, suggesting a possible role for these RNP complexes in positive-strand viral RNA synthesis. We used retrovirus-mediated expression of hnRNP C-specific short hairpin RNAs (shRNAs) to reduce the levels of hnRNP C proteins in HeLa cells. Poliovirus yields were decreased five-fold in hnRNP C-specific shRNA-treated cells compared to infections of control shRNA-treated cells. Quantitative real-time PCR analysis revealed that the accumulation of positive-strand RNA was selectively decreased in hnRNP C-depleted cells during the early phases of poliovirus infection. Our results suggest that cellular hnRNP C proteins play an important role in the formation of positive-strand RNA replication complexes in infected cells. In addition to generating mechanistic insights into picornavirus-host cell interactions, results from our studies should identify molecular targets for antiviral therapies as well as the nature of specific macromolecular interactions that regulate viral gene expression.
Publications:
Bedard, K. M., Daijogo, S., and Semler, B. L. A nucleo-cytoplasmic SR protein functions in viral IRES-mediated translation initiation. EMBO J. 26:459-467 (2007)
 
Perera, R., Daijogo, S., Walter, B. L., Nguyen, J. H. C., and Semler, B. L. Cellular protein modification by poliovirus: the two faces of poly(rC)-binding protein. J. Virol. 81:8919-8932 (2007)
 
Semler, B. L., and Waterman, M. L. IRES-mediated pathways to polysomes: nuclear versus cytoplasmic routes. Trends Microbiol. 16:1-5 (2008)
 
Sean, P., and Semler, B. L. Coxsackievirus B RNA replication: lessons from poliovirus. Curr. Top. Microbiol. Immunol. 323:89-121 (2008)
 
Sean, P., Nguyen, J. H. C., and Semler, B. L. The linker domain of poly(rC) binding protein 2 is a major determinant in poliovirus cap-independent translation. Virology 378:243-253 (2008)
 
Sean, P., Nguyen, J. H. C., and Semler, B. L. Altered interactions between stem-loop IV within the 5' noncoding region of coxsackievirus RNA and poly(rC) binding protein 2: effects on IRES-mediated translation and viral infectivity. Virology 389:45-58 (2009)
 
Fitzgerald, K. D., and Semler, B. L. Bridging IRES elements in mRNAs to the eukaryotic translation apparatus. Biochim. Biophys. Acta 1789:518-528 (2009)
 
Brunner, J. E., Ertel, K. J., Rozovics, J. M., and Semler, B. L. Delayed kinetics of poliovirus RNA synthesis in a human cell line with reduced levels of hnRNP C proteins. Virology 400:240-247 (2010)
 
Ertel, K. J., Brunner, J. E., and Semler, B. L. Mechanistic consequences of hnRNP C binding to both RNA termini of poliovirus negative-strand RNA intermediates. J. Virol. 84:4229-4242 (2010)
 
Grainger, L., Cicchini, L., Rak, M., Petrucelli, A., Fitzgerald, K. D., Semler, B. L., and Goodrum, F. Stress-inducible alternative translation initiation of human cytomegalovirus latency protein pUL138. J. Virol. 84: 9472-9486 (2010)
 
Rozovics, J. M., Virgen-Slane, R., and Semler, B. L. Engineered picornavirus VPg-RNA substrates: analysis of a tyrosyl-RNA phosphodiesterase activity. PLoS ONE 6:e16559 (2011)
 
Daijogo, S., and Semler, B. L. Mechanistic intersections between picornavirus translation and RNA replication. Adv Virus Res. 80:1-24 (2011)
 
Fitzgerald, K. D., and Semler, B. L. Re-localization of cellular protein SRp20 during poliovirus infection: bridging a viral IRES to the host cell translation apparatus. PLoS Pathog. 7:e1002127 (2011)
 
Huang, C., Lokugamage, K. G., Rozovics, J. M., Narayanan, K., Semler, B. L., and Makino, S. SARS coronavirus nsp1 protein induces template-dependent endonucleolytic cleavage of mRNAs: viral mRNAs are resistant to nsp1-induced RNA cleavage. PLoS Pathog. 7:e1002433 (2011)
 
Virgen-Slane, R., Rozovics, J. M., Fitzgerald, K. D., Ngo, T., Chou, W., van der Heden van Noort, G. J., Filippov, D. V., Gershon, P. D., and Semler, B. L. An RNA virus hijacks an incognito function of a DNA repair enzyme. Proc. Natl. Acad. Sci. USA 109:14634-14639 (2012)
 
Chase, A. J., and Semler, B. L. Viral subversion of host functions for picornavirus translation and RNA replication. Future Virol. 7:179-191 (2012)
 
Rozovics, J. M., Chase, A. J., Cathcart, A. L., Chou, W., Gershon, P. D., Palusa, S., Wilusz, J., and Semler, B. L. Picornavirus modification of a host mRNA decay protein. mBio, 3(6):e00431-12 (2012)
 
Feng, Q., Hato, S. V., Langereis, M. A., Zoll, J., Virgen-Slane, R., Peisley, A., Hur, S., Semler, B. L., van Rij, R. P., and van Kuppeveld, F. J. M. MDA5 detects the double-stranded RNA replicative form in picornavirus-infected cells. Cell Rep. 2:1187-1196 (2012)
 
Fitzgerald, K. D., Chase, A. J., Cathcart, A. L., Tran, G. P., and Semler, B. L. Viral proteinase requirements for the nucleo-cytoplasmic re-localization of cellular splicing factor SRp20 during picornavirus infections. J. Virol. 87:2390-2400 (2013)
Professional
Societies
American Society for Microbiology
American Society for Virology
RNA Society
American Society for Biochemistry and Molecular Biology
 
Address
University of California
Medical Sciences I, B-237
Mail Code: 4025
Irvine, CA 92697
Phone:
(949) 824-7573
Fax:
(949) 824-2694
Email:
blsemler@uci.edu
URLs
Department of Microbiology and Molecular Genetics
Center for Virus Research
Graduate Program in Cellular and Molecular Biosciences
Updated 04/29/2013

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