Critical cellular processes are controlled through regulated degradation of proteins via the ubiquitin proteasome system. The E3 ubiquitin ligase is the final enzyme in the ubiquitination reaction that transfers ubiquitin molecules to the protein substrate targeted for degradation. My lab has two ongoing research projects, both related to ubiquitin:
1. The ubiquitin proteasome system is frequently co-opted by viruses to target either cellular or viral proteins for proteasomal degradation. The genome of Kaposi’s sarcoma herpesvirus (KSHV) encodes a number of proteins that act directly as ubiquitin ligases, act as a subunit of a ubiquitin ligase, enhance the stability of a cellular ubiquitin ligase or in some way affect the activity of a ubiquitin ligase. RTA is the key activator of the switch from latent to lytic replication. In addition to activating lytic gene expression, RTA has also been assigned ubiquitin ligase activity and has was reported to stabilize the cellular E3, RAUL. We are working to identify different protein substrates of the RTA ubiquitin ligase as well as cellular ubiquitin ligases that are recruited or stabilized by RTA.
2. Cul5 is an E3 ubiquitin ligase that is frequently hijacked by viruses. Cul5 has been co-opted by HIV, Adenovirus, KSHV, and HPV. We have previously reported a cellular function of Cul5 in regulation of Hsp90 client proteins. Hsp90 clients are frequently dysregulated in cancer; in fact Hsp90 is required to maintain the oncogenic state of multiple types of cancer cells. We are interested in exploring the role of Cul5 expression in cancer diagnosis, prognosis and sensitivity to chemotherapy.
My lab is currently recruiting graduate students.
Ehrlich, E. , T. Wang, K. Luo, Z. Xiao, A. M. Niewiadomska, T. Martinez, W. Xu, L. Neckers & X.-F. Yu. 2009. Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase. Proc Natl Acad Sci USA 106::20330-20335.
Jayaram S., T. Gilson, E. S. Ehrlich, X.-F. Yu, G. Ketner & L. Hanakahi. 2008. E1B 55k-independent dissociation of the DNA ligase IV/XRCC4 complex by E4 34k during adenovirus infection. Virology 382:163-70.
Stanley, B. J., E. S. Ehrlich, L. Short, Y. Yu, Z. Xiao, X.-F. Yu, & Y. Xiong. 2008. Structural Insight into the HIV Vif SOCS Box and Its Role in Human E3 Ubiquitin Ligase Assembly. J Virol 82:8656–8663.
Xiao, Z. , Y. Xiong, W. Zhang, L. Tan, E. Ehrlich, D. Guo, & X.-F. Yu. 2007. Characterization of a Novel Cullin5 Binding Domain in HIV-1 Vif. J Mol Biol 373:541-50.