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
- Vice-Chair, Institute for Molecular Virology
- Assistant Director, McArdle Laboratory for Cancer Research
- Member, Virology – B study section
- Associate Editor, PLoS Pathogens
- Editorial Board, The Journal of Virology
- Penkert, RR, and Kalejta, R (2013).Human Embryonic Stem Cell Lines Model Experimental Human Cytomegalovirus Latency. mBio. 2013 May 28;4(3):e00298-13. PMID: 23716573
- Qin Q, Lee SH, Liang R, Kalejta RF. 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. 2014 Jan 5;448:125-32. PMID: 24314643
- Winkler LL, Kalejta RF. The 19S proteasome activator promotes human cytomegalovirus immediate early gene expression through proteolytic and nonproteolytic mechanisms.
- J Virol. 2014 Oct;88(20):11782-90. doi: 10.1128/JVI.01720-14. Epub 2014 Jul 30. PMID: 25078702
- 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. PMID: 25694602
- 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 Jun 21. pii: jbc.M115.660043. [Epub ahead of print] PMID: 26100623