Bert L. Semler

picture of Bert L. Semler

Distinguished Professor, Microbiology & Molecular Genetics
School of Medicine

Director, Center for Virus Research


B.S., University of California, Irvine, 1974
Ph.D., University of California, San Diego, 1979

Phone: (949) 824-7573
Fax: (949) 824-2694
Email: blsemler@uci.edu

University of California, Irvine
Medical Sciences I, B-237
Mail Code: 4025
Irvine, CA 92697
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
URLs
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; American Society for Microbiology Distinguished Lecturer
Appointments
Postdoctoral Fellow, Department of Microbiology, State University of New York at Stony Brook, 1979-1983
Research Abstract
Our research is focused on how picornaviruses employ unique mechanisms for key steps in viral translation initiation and genomic RNA replication in infected human cells. Picornaviruses are positive-strand RNA viruses that include important agents of human disease such as human rhinovirus, coxsackievirus, poliovirus, enterovirus D68, and hepatitis A virus. Our research in picornavirus molecular biology has broken new ground in the areas of protein processing, IRES-mediated translation initiation, viral RNA replication mechanisms, and RNA virus-host interactions. My laboratory colleagues and I have studied how picornaviruses allow ribosome clearance on translating viral genomic RNAs prior to the onset of viral RNA replication. We demonstrated the multi-functional role of a cellular RNA binding protein (PCBP2) in both translation initiation and viral RNA replication during picornavirus infections, genetically linking these two critical processes for the first time. Importantly, our data suggested that interactions between PCBP2 and picornavirus-encoded proteinases mediate, in part, the switch from viral translation to RNA replication using the same genomic RNA template. In analyzing host cell functions required for picornavirus replication, we identified a novel host cell enzyme that cleaves a protein-RNA linkage between a small viral protein (called VPg) and the 5’ end of genomic RNA during poliovirus infection. This enzyme, tyrosyl-DNA phosphodiesterase 2 (TDP2), is normally involved in host cell DNA repair, transcriptional regulation, and intracellular signaling. We have used genetic ablation studies to determine the role of this enzyme during the picornavirus replication cycle. Our results uncovered a differential requirement for TDP2 by different picornaviruses and have suggested a post-translational role for this protein in picornavirus infections of human cells. Understanding this role may lead to novel anti-viral therapeutics targeting a unique virus-host interface.

In ongoing experiments, we are using RNA/protein affinity approaches and mass spectrometry to elucidate the mechanisms of viral RNA replication complex assembly and dynamics in cells infected by poliovirus or human rhinovirus. Such approaches have already led to the identification of a host cell protein (AUF1) involved in mRNA decay as part of viral RNP complexes whose composition and biological activity change during the course of infection. We have also taken an unbiased proteomics approach to identify host cell nuclear proteins that re-localize to the cytoplasm of HeLa cells during infection with human rhinovirus. Among the numerous host proteins whose abundance in the nucleus during rhinovirus infection clearly decreased, concomitant with an increase in cytoplasmic levels, we identified splicing factor proline and glutamine rich (SFPQ), a large multi-functional protein involved in numerous cellular processes (e.g., splicing, transcription, DNA repair). Understanding the role of such proteins continues to provide significant mechanistic insights into how positive-strand RNA viruses recruit host proteins for both viral translation initiation and RNA replication, thereby expanding the repertoire of functions for these viruses with a very limited coding capacity.

More recently, we have initiated projects in three additional areas of RNA virus research: (1) Understanding the molecular basis of enterovirus persistence in cardiac cells; (2) Generation of novel rabies virus vectors for neuronal circuit tracing; and (3) Development of novel therapeutics against SARS-CoV-2. These projects use a wide range of state-of-the-art experimental tools in molecular virology and cell biology. They also take advantage of our significant experience in the study of virus-host interactions and the genetic and biochemical determinants of RNA virus replication.
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)
 
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)
 
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)
 
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)
 
Cathcart, A. L., Rozovics, J. M., and Semler, B. L. Cellular mRNA decay protein AUF1 negatively regulates enterovirus and human rhinovirus infections. J. Virol. 87:10423-10434 (2013)
 
Chase, A. J., and Semler, B. L. Differential cleavage of IRES trans-acting factors (ITAFs) in cells infected by human rhinovirus. Virology 449:35-44 (2014)
 
Langereis, M. A., Feng, Q., Nelissen, F., Virgen-Slane, R., van der Heden van Noort, G. J., Maciejewski, S., Filippov, D. V., Semler, B. L., van Delft, F., and van Kuppeveld, F. J. Modification of picornavirus genomic RNA using ‘click’ chemistry shows that unlinking of the VPg peptide is dispensable for translation and replication of the incoming viral RNA. Nucleic Acids Res. 42:2473-2482 (2014)
 
Chase, A. J., Daijogo, S., and Semler, B. L. Inhibition of poliovirus-induced cleavage of cellular protein PCBP2 reduces the levels of viral RNA replication. J. Virol. 88:3192-3201 (2014)
 
Cathcart, A. L., and Semler, B. L. Differential restriction patterns of mRNA decay factor AUF1 during picornavirus infections. J. Gen. Virol. 95:1488-1492 (2014)
 
Tsai, B. P., Jimenez, J., Lim, S., Fitzgerald, K. D., Zhang, M., Chuah, C. T., Axelrod, H., Wilson, L., Ong, S. T., Semler, B. L., and Waterman, M. L. A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1. Open Biol. 4:140180 (2014)
 
Lévêque, N., and Semler, B.L. A 21st century perspective of poliovirus replication. PLoS Pathog. 11:e1004825 (2015)
 
Flather, D. and Semler, B.L. Picornaviruses and nuclear functions: targeting a cellular compartment distinct from the replication site of a positive-strand RNA virus. Front. Microbiol. 6:594 (2015)
 
Hopcraft, S. E., Azarm, K. D., Israelow, B., Lévêque, N., Schwarz, M. C., Hsu, T.-H., Chambers, M. T., Sourisseau, M., Semler, B. L., and Evans, M. Viral determinants of miR- 122-independent hepatitis C virus replication. mSphere 1(1): e00009-15 (2015)
 
Maciejewski, S., Nguyen, J. H. C., Gómez-Herreros, F., Cortés-Ledesma, F., Caldecott, K. W., and Semler, B. L. Divergent requirement for a DNA repair enzyme during enterovirus infections. mBio 7(1):e01931-15 (2015)
 
Flather, D., Cathcart, A. L., Cruz, C., Baggs, E., Ngo, T., Gerhson, P. D., and Semler, B. L. Generation of recombinant polioviruses harboring RNA affinity tags in the 5' and 3' noncoding regions of genomic RNAs. Viruses 8(2):39 (2016)
 
Ullmer, W. and Semler, B. L. Diverse strategies used by picornaviruses to escape host RNA decay pathways. Viruses 8:335 (2016)
 
Karginov, T. A., Pastor, D. P., Semler, B. L., and Gomez, C. M. Mammalian polycistronic mRNAs and disease. Trends Genet. 33:129-142 (2017)
 
Lévêque, N., Garcia, M., Bouin, A., Nguyen, J. H. C., Tran, G. P., Andreoletti, L., and Semler, B. L. Functional consequences of RNA 5' terminal deletions on coxsackievirus B3 RNA replication and ribonucleoprotein complex formation. J. Virol. 91(16): e00423-17 (2017)
 
Maciejewski, S., Ullmer, W., and Semler, B. L. VPg unlinkase/TDP2 in cardiovirus infected cells: re-localization and proteolytic cleavage. Virology 516:139-146 (2018)
 
Ullmer, W. and Semler, B. L. Direct and indirect effects on viral translation and RNA replication are required for AUF1 restriction of enterovirus infections in human cells. mBio 9(5):e01669-18 (2018)
 
Maciejewski, S., and Semler, B. L. Hijacking host functions for translation and RNA replication by enteroviruses, pp. 23-49. In: W. Jackson and C. Coyne, eds. Enteroviruses: Omics, Molecular Biology, and Control, Caister Academic Press; Poole, U.K. (2018)
 
Flather, D., Nguyen, H. C., Semler, B. L., and Gershon, P.D. Exploitation of nuclear functions by human rhinovirus, a cytoplasmic RNA virus. PLoS Pathog. 14:e1007277 (2018)
 
Bouin, A., Gretteau, P. A., Wehbe, M., Renois, F., N’guyen, Y., Lévêque, N., Vu, M., Tracy, S., Chapman, N. M., Bruneval, P., Fornes, P., Semler, B. L., and Andreoletti, L. Enterovirus persistence in cardiac cells of patients suffering from idiopathic dilated cardiomyopathy is linked to 5' terminal genomic RNA-deleted viral populations with viral-encoded proteinase activities. Circulation 139:2326-2338 (2019)
 
Holmes, A. C., and Semler, B. L. Picornaviruses and RNA metabolism: local and global effects of infection. J. Virol. 93(21): e02088-17 (2019)
 
Holmes, A. C., Zagnoli-Vieira, G., Caldecott, K. W., and Semler, B. L. Effects of TDP2/VPg unlinkase activity on picornavirus infections downstream of virus translation. Viruses 12:166 (2020)
 
Beckham. S. A., Matak, M. Y., Belousoff, M. J., Venugopal, H., Shah, N., Vankadari, N., Elmlund, H., Nguyen, J. H. C., Semler, B. L., Wilce, M. C. J., and Wilce, J. A. Structure of the PCBP2/stem-loop IV complex underlying translation initiation mediated by the poliovirus type I IRES. Nucleic Acids Res. 48:8006–8021 (2020).
 
Bouin, A., and Semler, B. L. Picornavirus cellular remodeling: doubling down in response to viral-induced inflammation. Curr. Clin. Microbiol. Rep. 7(2):31-37 (2020)
 
Xu, X., Holmes, T. C., Luo, M. H., Beier, K. T., Horwitz, G. D., Zhao, F., Zeng, W., Hui, M., Semler, B. L., and Sandri-Goldin, R. M. Viral vectors for neural circuit mapping and recent advances in trans-synaptic anterograde tracers. Neuron 107(6):1029-1047 (2020)
Grants
National Institutes of Health, “Virus-host interactions: a multi-scale training program,” T32 Pre-doctoral graduate student training grant, 9/1/20-8/31/25 (current funding period)
National Institutes of Health, “Impact of host protein dynamics on picornavirus RNA 5’ noncoding region functions,” 4/22/16-3/31/21 (current funding period)
National Institutes of Health, “Synthesis of enterovirus positive-strand RNAs: discovery of viral and host determinants of RNP complex formation,” 01/01/20-12/31/21 (current funding period)
Professional Societies
American Society for Microbiology
American Society for Virology
RNA Society
American Society for Biochemistry and Molecular Biology
Graduate Programs
Cellular and Molecular Biosciences

Research Center
Center for Virus Research
Last updated
10/25/2020