B.S., 1990, Biochemistry, Penn State University
Ph.D., 1997, Biochemistry, University of Virginia
Postdoctoral research: Princeton University
Our lab focuses on determining the mechanisms of human cytomegalovirus (HCMV) replication and pathogenesis, and also uses the virus as a tool to probe the pathways that lead to cell cycle progression and oncogenesis. 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. As an obligate intracellular parasite, HCMV relies upon its host cell for its replication. Thus, to promote its own survival, HCMV has evolved ways to commandeer cellular pathways such as cell cycle progression, transcriptional silencing, and protein degradation.
We study two HCMV proteins that stimulate cell cycle progression by inactivating the retinoblastoma (Rb) tumor suppressor protein by two distinct mechanisms. The pp71 protein induces Rb degradation and the UL97 protein directly phosphorylates Rb.
pp71 induces protein degradation 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. We are interested in further characterizing the interaction of pp71 with the Rb tumor suppressor and the role of this interaction during viral infection and cellular transformation. 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.
Finally, we are beginning to explore mechanisms of HCMV pathogenesis. In particular we are interested in potential roles for HCMV infection in cancers, most notably glioblastomas. HCMV DNA genomes and protein antigens are found in the majority of glioblastomas. Because HCMV encodes proteins that can induce inflammation, thwart the immune system, prevent apoptosis, promote angiogenesis, and stimulate cell cycle progression, we are initiating a translational research project investigating the oncomodulatory functions of HCMV.
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.
Umaña AC, Iwahori S, Kalejta RF. Direct Substrate Identification with an Analog Sensitive (AS) Viral Cyclin-Dependent Kinase (v-Cdk). ACS Chem Biol. 2018 Jan 19;13(1):189-199. doi: 10.1021/acschembio.7b00972. Epub 2017 Dec 19. PubMed PMID: 29215867; PubMed Central PMCID: PMC5777508.
Iwahori S, Kalejta RF. Phosphorylation of transcriptional regulators in the retinoblastoma protein pathway by UL97, the viral cyclin-dependent kinase encoded by human cytomegalovirus. Virology. 2017 Dec;512:95-103. doi: 10.1016/j.virol.2017.09.009. PubMed PMID: 28946006; PubMed Central PMCID: PMC5653418.
Iwahori S, Umaña AC, VanDeusen HR, Kalejta RF. Human cytomegalovirus-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates and inactivates the retinoblastoma protein-related p107 and p130 proteins. J Biol Chem. 2017 Apr 21;292(16):6583-6599. doi: 10.1074/jbc.M116.773150. Epub 2017 Mar 13. PubMed PMID: 28289097; PubMed Central PMCID: PMC5399109.
Kalejta RF, Palmenberg AC. Gender parity trends for invited speakers at four prominent virology conference series. J Virol. 2017 Jun 7. pii: JVI.00739-17. doi: 10.1128/JVI.00739-17. [Epub ahead of print] PubMed PMID: 28592542; PubMed Central PMCID: PMC5533912.
Liu C, Clark PA, Kuo JS, Kalejta RF. Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes. mSphere. 2017 Jun 21;2(3). pii: e00137-17. doi: 10.1128/mSphere.00137-17. eCollection 2017 May-Jun. PubMed PMID: 28656174; PubMed Central PMCID: PMC5480031.
Albright ER, Kalejta RF. Canonical and variant forms of histone H3 are deposited onto the human cytomegalovirus genome during lytic and latent infections. J Virol. 2016 Nov;90(22):10309-20. PubMed PMID: 27605676; PubMed Central PMCID: PMC5105665.
Kalejta RF. Sifting and Winnowing through Human Cytomegalovirus Lytic Replication and Latency. PLoS Pathog. 2016 Sep 22;12(9):e1005607. doi: 10.1371/journal.ppat.1005607. PubMed PMID: 27657905; PubMed Central PMCID: PMC5033567.
Kuny CV, Kalejta RF. Human Cytomegalovirus Can Procure Deoxyribonucleotides for Viral DNA Replication in the Absence of Retinoblastoma Protein Phosphorylation. J Virol. 2016 Sep 12;90(19):8634-43. doi: 10.1128/JVI.00731-16. Print 2016 Oct 1. PubMed PMID: 27440891; PubMed Central PMCID: PMC5021408.
Lee SH, Caviness K, Albright ER, Lee JH, Gelbmann CB, Rak M, Goodrum F, Kalejta RF. Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency. J Virol. 2016 Sep 29;90(20):9483-94. doi: 10.1128/JVI.01547-16. PubMed PMID: 27512069; PubMed Central PMCID: PMC5044833.
Lee WH, Higuchi H, Ikeda S, Macke EL, Takimoto T, Pattnaik BR, Liu C, Chu LF, Siepka SM, Krentz KJ, Rubinstein CD, Kalejta RF, Thomson JA, Mullins RF, Takahashi JS, Pinto LH, Ikeda A. Mouse Tmem135 mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies. Elife. 2016 Nov 15;5. pii: e19264. doi: 10.7554/eLife.19264. PubMed PMID: 27863209; PubMed Central PMCID: PMC5117855.
Iwahori S, Hakki M, Chou S, Kalejta RF. Molecular Determinants for the Inactivation of the Retinoblastoma Tumor Suppressor by the Viral Cyclin-dependent Kinase UL97. J Biol Chem. 2015 Aug 7;290(32):19666-80. doi: 10.1074/jbc.M115.660043. Epub 2015 Jun 21. PubMed PMID: 26100623; PubMed Central PMCID: PMC4528131.
Lee SH, Albright ER, Lee JH, Jacobs D, Kalejta RF. Cellular defense against latent colonization foiled by human cytomegalovirus UL138 protein. Sci Adv. 2015 Nov 27;1(10):e1501164. doi: 10.1126/sciadv.1501164. eCollection 2015 Nov. PubMed PMID: 26702450; PubMed Central PMCID: PMC4681346.
VanDeusen HR, Kalejta RF. Deficiencies in Cellular Processes Modulated by the Retinoblastoma Protein Do Not Account for Reduced Human Cytomegalovirus Replication in Its Absence. J Virol. 2015 Dec 1;89(23):11965-74. doi: 10.1128/JVI.01718-15. Epub 2015 Sep 16. PubMed PMID: 26378180; PubMed Central PMCID: PMC4645314.
VanDeusen HR, Kalejta RF. The retinoblastoma tumor suppressor promotes efficient human cytomegalovirus lytic replication. J Virol. 2015 May;89(9):5012-21. doi: 10.1128/JVI.00175-15. Epub 2015 Feb 18. PubMed PMID: 25694602; PubMed Central PMCID: PMC4403481.
Qin, Q., Lee, S. H., Liang, R., and Kalejta, R. F. Insertion of Myeloid-Active Elements Into the Human Cytomegalovirus Major Immediate Early Promoter Is Not Sufficient to Drive Its Activation Upon Infection of Undifferentiated Myeloid Cells. Virology, 448: 125-132, 2014.
Winkler, L. L., and Kalejta, R. F. The 19S Proteasome Activator Promotes Human Cytomegalovirus Immediate Early Gene Expression through Proteolytic and Nonproteolytic Mechanisms. J. Virol., 88(20): 11782-11790, 2014.
Albright, E. R., and Kalejta, R. F. Myeloblastic Cell Lines Mimic Some But Not All Aspects of Human Cytomegalovirus Experimental Latency Defined in Primary CD34+ Cell Populations. J. Virol., 87(17): 9802-9812, 2013.
Kalejta, R. F. Pre-Immediate Early Tegument Protein Functions. In: M. J. Reddehase (Ed.), Cytomegaloviruses: From Molecular Pathogenesis to Intervention, Volume 1, Chapter 9, pp. 141-151. Norfolk, UK: Caister Academic Press, 2013.
Penkert, R. R., and Kalejta, R. F. Human Embryonic Stem Cell Lines Model Experimental Human Cytomegalovirus Latency. mBio, 4(3):e00298-13, 2013.
Qin, Q., Penkert, R. R., and Kalejta, R. F. Heterologous Viral Promoters Incorporated Into the Human Cytomegalovirus Genome Are Silenced during Experimental Latency. J. Virol., 87(17): 9886-9894, 2013.
Sun, X., Bristol, J. A., Iwahori, S., Hagemeier, S. R., Meng, Q., Barlow, E. A., Fingeroth, J. D., Tarakanova, V. L., Kalejta, R. F., and Kenney, S. C. Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells. J. Virol., 87(18): 10126-10138, 2013.
Winkler, L. L., Hwang, J., and Kalejta, R. F. Ubiquitin-Independent Proteasomal Degradation of Tumor Suppressors by Human Cytomegalovirus pp71 Requires the 19S Regulatory Particle. J. Virol., 87(8): 4665-4671, 2013.
Dziurzynski, K., Chang, S. M., Heimberger, A. B., Kalejta, R. F., McGregor Dallas, S. R., Smit, M., Soroceanu, L., Cobbs, C. S., the HCMV and Gliomas Symposium. Consensus on the Role of Human Cytomegalovirus in Glioblastoma. Neuro Oncol., 14: 246-255, 2012.
Lee, S. H., Kalejta, R. F., Kerry, J., Semmes, O. J., O’Connor, C. M., Khan, Z., Garcia, B. A., Shenk, T., and Murphy, E. BclAF1 Restriction Factor Is Neutralized by Proteasomal Degradation and microRNA Repression during Human Cytomegalovirus Infection. Proc. Natl. Acad. Sci. USA, 109: 9575-9580, 2012.
Penkert, R. R., and Kalejta, R. F. Tale of a Tegument Transactivator: The Past, Present and Future of Human CMV pp71. Future Virol., 7: 855-869, 2012.
Ranganathan, P., Clark, P. A., Kuo, J. S., Salamat, M. S., and Kalejta, R. F. Significant Association of Multiple Human Cytomegalovirus Genomic Loci with Glioblastoma Multiforme Samples. J. Virol., 86: 854-864, 2012.
Member, National Institutes of Health Virology B Study Section, 2011-2015