Faculty: Robert Kalejta
|Dept:||Associate Professor, Oncology and Molecular Virology|
|Training Areas:||Molecular & Cellular Pharmacology|
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
- NIH Cell and Molecular Biology Training Grant T32 GM08136, 1993-1996
- Leukemia and Lymphoma Society Fellow, 1997-2000
- American Heart Association Scientist Development Grant, 2004-2007
- Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease, 2006-2011
- Editorial Board, The Journal of Virology, 2010-2012
- Editorial Board, Herpesviridae, 2010-present
- Ad-hoc NIH VIRA study section, Feb 2010, Oct 2010
- Winkler LL, Hwang J, Kalejta RF. Ubiquitin-independent proteasomal degradation of tumor suppressors by human cytomegalovirus pp71 requires the 19S regulatory particle. J Virol. 2013 Feb 13. PMID: 23408605
- Penkert RR, Kalejta RF. Tale of a tegument transactivator: the past, present and future of human CMV pp71. Future Virol. 2012 Sep 1;7(9):855-869. PMID: 23378857
- Lee SH, Kalejta RF, Kerry J, Semmes OJ, O'Connor CM, Khan Z, Garcia BA, Shenk T, Murphy E. BclAF1 restriction factor is neutralized by proteasomal degradation and microRNA repression during human cytomegalovirus infection. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9575-80. doi: 10.1073/pnas.1207496109. Epub 2012 May 29. PMID: 22645331
- Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor Dallas SR, Smit M, Soroceanu L, Cobbs CS; HCMV and Gliomas Symposium. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 2012 Mar;14(3):246-55. doi: 10.1093/neuonc/nor227. Epub 2012 Feb 8. PMID: 22319219
- Ranganathan P, Clark PA, Kuo JS, Salamat MS, Kalejta RF. Significant association of multiple human cytomegalovirus genomic Loci with glioblastoma multiforme samples. J Virol. 2012 Jan;86(2):854-64. doi: 10.1128/JVI.06097-11. Epub 2011 Nov 16. PMID: 22090104
- Hwang J, Kalejta RF (2011).In vivo analysis of protein sumoylation induced by a viral protein: Detection of HCMV pp71-induced Daxx sumoylation. Methods. 55(2):160-5. PMID: 21816224
- Hwang J, Saffert RT, Kalejta RF (2011). Elongin B-mediated epigenetic alteration of viral chromatin correlates with efficient human cytomegalovirus gene expression and replication. MBio. 2(2):e00023-11. doi: 10.1128/mBio.00023-11. Print 2011. PMID: 21447700
- Kuny, C.V., Chinchilla, K., Culbertson, M.R., and Kalejta, R.F. (2010)
Cyclin-dependent kinase-like function is shared by the beta- and gamma- subset of the conserved herpesvirus protein kinases. PLoS Pathog 6(9): e1001092. doi10.1371/journal.ppat.1001092. PMCID: in process
- Penkert, R.R., and Kalejta, R.F. (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 (19) 9853-63. PMCID: in process
- Saffert, R.T., Penkert, R.R., and Kalejta, R.F. (2010) Cellular and viral control over the initial events of human cytomegalovirus experimental latency in CD34+ cell. J. Virol. 84 (11) 5594-5604. PMCID: PMC2876595
- Meng, Q., Hagemeier, S.R., Kuny, C.V., Kalejta, R.F., and Kenney, S.C. (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 (9) 4524-4533. PMCID: PMC2863785