Faculty: Robert Kalejta
|Dept:||Associate Professor, Oncology and Molecular Virology|
|Lab Website:||Click Here|
Our lab focuses on determining the mechanisms of human cytomegalovirus (HCMV) replication and pathogenesis. We are interested in HCMV because it is a ubiquitous and medically relevant virus that causes severe disease in immunocompromised patients, is the leading viral cause of birth defects, and impacts upon the etiology and/or progression of cardiovascular disease and cancer.
Viruses are obligate intracellular parasites that rely upon their host cells for its replication. Therefore, viruses have an intimate knowledge of the inner workings of cells. They are the best cell biologists you will ever meet. Thus, studying how a virus manipulates a cellular pathway or process you are interested in is a great way to learn more about it. Our interests are cell cycle progression, transcriptional silencing, and protein degradation. We study two HCMV proteins that modulate these pathways called pp71 and UL97.
pp71 induces the degradation of cellular proteins that it binds to in an unusual, proteasome-dependent but ubiquitin independent manner. We are actively exploring the mechanism through which it accomplishes this important task. pp71 degrades the Rb tumor suppressor that controls progression through the G1 phase of the cell cycle. By degrading Rb, pp71 stimulates cell cycle progression. pp71 also degrades Daxx, and thus neutralizes a cellular intrinsic antiviral defense mediated by this nuclearly localized protein, allowing for viral gene expression during lytic HCMV infections. Interestingly, the virus prevents pp71-mediated degradation of Daxx during the establishment of latent infections by sequestering pp71 in the cytoplasm of infected cells. Determining how pp71 is trapped in the cytoplasm is a major goal of the laboratory.
UL97 is a protein kinase, and we identified it as the first known viral protein that directly phosphorylates Rb. Furthermore, we found that UL97 mimics the activities of the cellular cyclin-dependent kinases (Cdks) that drive cell cycle progression, thus identifying UL97 as the first viral Cdk (v-Cdk). Our lab is continuing to study how UL97 phosphorylates Rb, stimulates cell cycle progression, and the role that these activities have during HCMV infection. An interesting corollary to these studies is that the cellular cyclin-dependent kinases (Cdks) that normally phosphorylate Rb are activated during HCMV infection but fail to phosphorylate Rb. We would like to determine how HCMV can prevent Cdk-mediated Rb phosphorylation, and then perhaps use that approach as a cancer chemotherapy.
A more detailed description of our work, information about the size and composition of our group and our complete publication record can be found on our Lab Home Page.
Honors & Awards
- Assistant Director for Oncology-Institute for Molecular Virology Liaison, 2011-present
- Member, Virology – B study section (NIH-CSR), 2011-2015
- Vilas Associate, 2011-2012
- Ad-hoc NIH VIRB study section, Feb 2011
- Ad-hoc NIH VIRA study section, Feb 2010
- Editorial Board, The Journal of Virology, 2010-2012
- Editorial Board, Herpesviridae, 2010-present
- Ad-hoc NIH VIRA study section, Feb 2010, Oct 2010
- Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease, 2006-2011
- American Heart Association Scientist Development Grant, 2004-2007
- Albright, ER, and Kalejta, RF (2013). Myeloblastic Cell Lines Mimic Some But Not All Aspects of Human Cytomegalovirus Experimental Latency Defined in Primary CD34+ Cell Populations. J. Virol. [Epub ahead of print Jul 3 2013].
- Penkert, RR, and Kalejta, R (2013). Human Embryonic Stem Cell Lines Model Experimental Human Cytomegalovirus Latency. mBio. 4:e00298-13
- Qin, Q, Penkert, RR and Kalejta RF (2013). Heterologous Viral Promoters Incorporated Into the Human Cytomegalovirus Genome Are Silenced during Experimental Latency. J. Virol. [Epub ahead of print Jul 3 2013].
- Sun X, Bristol JA, Iwahori S, Hagemeier SR, Meng Q, Barlow EA, Fingeroth JD, Tarakanova VL, Kalejta RF, and Kenney SC (2013). Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-infected Cells. J. Virol. [Epub ahead of print Jul 10 2013].
- Winkler LL, Hwang J, and Kalejta RF. Ubiquitin-independent proteasomal degradation of tumor suppressors by human cytomegalovirus pp71 requires the 19S regulatory particle. J Virol. 87:4665-4671. PMID: 23408605
- Penkert RR, Kalejta RF (2012). Tale of a tegument transactivator: the past, present and future of human CMV pp71. Future Virol. 7:855-869. PMID: 23378857
- Lee SH, Kalejta RF, Kerry J, Semmes OJ, O'Connor CM, Khan Z, Garcia BA, Shenk T, and Murphy E (2012). BclAF1 restriction factor is neutralized by proteasomal degradation and microRNA repression during human cytomegalovirus infection. Proc Natl Acad Sci USA. 109:9575-80. Epub 2012 May 29. PMID: 22645331
- Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor Dallas SR, Smit M, Soroceanu L, and Cobbs CS (2012). HCMV and Gliomas Symposium. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 14:246-55. Epub 2012 Feb 8. PMID: 22319219
- Ranganathan P, Clark PA, Kuo JS, Salamat MS, and Kalejta RF (2012). Significant association of multiple human cytomegalovirus genomic Loci with glioblastoma multiforme samples. J Virol. 86:854-64. Epub 2011 Nov 16. PMID: 22090104
- Hwang J and Kalejta RF (2011). In vivo analysis of protein sumoylation induced by a viral protein: Detection of HCMV pp71-induced Daxx sumoylation. Methods. 55:160-5. PMID: 21816224
- Hwang J, Saffert RT, and Kalejta RF (2011). Elongin B-mediated epigenetic alteration of viral chromatin correlates with efficient human cytomegalovirus gene expression and replication. MBio. 2:e00023-11. Print 2011. PMID: 21447700
- Kuny CV, Chinchilla K, Culbertson MR, and Kalejta RF (2010)
Cyclin-dependent kinase-like function is shared by the beta- and gamma- subset of the conserved herpesvirus protein kinases. PLoS Pathog 6: e1001092. PMCID: in process
- Penkert RR and Kalejta RF (2010). Nuclear localization of tegument-
delivered pp71 in human cytomegalovirus infected cells is facilitated by one or more factor present in terminally differentiated fibroblasts. J. Virol. 84:9853-63. PMCID: in process
- Saffert RT, Penkert RR, and Kalejta RF (2010). Cellular and viral control over the initial events of human cytomegalovirus experimental latency in CD34+ cell. J. Virol. 84:5594-5604. PMCID: PMC2876595
- Meng Q, Hagemeier SR, Kuny CV, Kalejta RF, and Kenney SC (2010). SV40 T/t antigens, and lamin A/C siRNA rescue the phenotype of an Epstein-Barr Virus (EBV) protein kinase (BGLF4) mutant. J. Virol. 84:4524-4533. PMCID: PMC2863785