Jon Huibregtse
| Title: | Associate Professor and Graduate Adviser Microbiology Graduate Program |  Video - PC Mac |
| Education: | Ph.D.: 1989, University of Michigan; B.S.: 1983, University of Michigan |
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| Postdoc.: | National Cancer Institute/NIH; Harvard Medical School | |
| Research: | Ubiquitin proteolysis system | |
| Office: | MBB 2.312AA | |
| Phone: | (512) 232-7700 Fax: (512) 232-3432 | |
| E-mail: | huibreg@mail.utexas.edu | |
| Postal Address: | Institute for Cellular and Molecular Biology The University of Texas at Austin 1 University Sta. A4800 Austin, TX 78712 |
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| Courses taught: | BIO 336/391M "Tumor Biology" BIO 393 "Function and Mechanisms of Ubiquitin Conjugation Pathways" |
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My lab is interested in the functions and substrate specificity of the ubiquitin proteolysis system and the role of the ubiquitin system in human papillomavirus (HPV)-associated cancers.
The ubiquitin proteolysis system is a major pathway for degradation of short-lived proteins in eukaryotic cells. This system functions through two basic sets of reactions: 1) the covalent linkage of ubiquitin, a 76 amino acid protein, to substrate proteins, and 2) the recognition and degradation of ubiquitinated proteins by the 26S proteasome. My laboratory is focused primarily on the first set of reactions, and on understanding how substrate specificity of the system is established and controlled.
Our interest in this problem arose from study of the human papillomavirus (HPV) E6 protein, one of two oncoproteins encoded by HPVs associated with uterine cervical cancer in women. Biochemical studies showed that the interaction of E6 with the p53 tumor suppressor leads to the targeted degradation of p53 through the ubiquitin proteolysis system. This led to the identification and characterization of a cellular protein, human E6AP, which was the first characterized member of a large family of proteins, now known as the HECT E3 proteins. These proteins play a direct role in substrate recognition as well as in catalyzing conjugation of ubiquitin to lysine side chains on substrates. Our current model is that the interaction of the HPV E6 protein with E6AP causes an alteration in the substrate specificity of E6AP, resulting in the ubiquitination and degradation of p53. The destruction of p53, a negative regulator of cell proliferation, is thought to promote the aberrant cell proliferation characteristic of HPV-containing neoplasias.
Our current research focuses on:
1) the role of the HPV E6 protein and E6AP in HPV-associated cancers,
2) the function of other HECT E3s in both mammalian and yeast cells, and
3) the biochemistry of the reactions catalyzed by HECT E3s.
In addition, we have recently begun a collaborative project with the lab of Dr. Robert Krug, examining the mechanism and function of conjugation of the ubiquitin-like protein, ISG15. ISG15 in an interferon-induced protein and is presumed to play a role in antiviral responses. Like ubiquitin, ISG15 becomes covalently ligated to cellular proteins, although ISG15 does not target proteins for destruction by the 26S proteasome. Other ubiquitin-like proteins (such as SUMO) have been previously shown to use parallel but distinct enzymatic pathways for conjugation. We have recently shown that the pathway for ISG15 conjugation actually converges with the ubiquitin conjugation pathway, and this has several important implications for function and regulation of ISG15 conjugation.
2005 |
Kelley ML, Keiger KE, Lee CJ, Huibregtse JM. The global transcriptional effects of the human papillomavirus E6 protein in cervical carcinoma cell lines are mediated by the E6AP ubiquitin ligase.
J Virol. 2005 Mar;79(6):3737-47. Kee Y, Lyon N, Huibregtse JM,
The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme.
EMBO J. 2005 Jul 6;24(13):2414-24.
2004 |
Shcherbik N, Kee Y, Lyon N, Huibregtse JM, Haines DS.
A single PXY motif located within the carboxyl terminus of Spt23p and Mga2p mediates a physical and functional interaction with ubiquitin ligase Rsp5p.
J Biol Chem. 2004 Dec 17;279(51):53892-8.
Zhao C, Beaudenon SL, Kelley ML, Waddell MB, Yuan W, Schulman BA, Huibregtse JM, Krug RM.
The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-{alpha}/{beta}-induced ubiquitin-like protein.
Proc Natl Acad Sci U S A. 2004 101:7578-7582.
Salvat C, Wang G, Dastur A, Lyon N, Huibregtse JM.
The -4 phenylalanine is required for substrate ubiquitination catalyzed by HECT ubiquitin ligases.
J Biol Chem. 2004 279:18935-43.
2002 |
Gao Q, Kumar A, Singh L, Huibregtse JM, Beaudenon S, Srinivasan S, Wazer DE, Band H, Band V.
Human papillomavirus E6-induced degradation of E6TP1 is mediated by E6AP ubiquitin ligase.
Cancer Res. 2002 62:3315-21.
2001 |
Harty RN, Brown ME, McGettigan JP, Wang G, Jayakar HR, Huibregtse JM, Whitt MA, Schnell MJ.
Rhabdoviruses and the cellular ubiquitin-proteasome system: a budding interaction.
J Virol. 2001 75:10623-9.
Wang G, McCaffery JM, Wendland B, Dupre S, Haguenauer-Tsapis R, Huibregtse JM.
Localization of the Rsp5p ubiquitin-protein ligase at multiple sites within the endocytic pathway.
Mol Cell Biol. 2001 21:3564-75.
2000 |
Harty RN, Brown ME, Wang G, Huibregtse J, Hayes FP.
A PPxY motif within the VP40 protein of Ebola virus interacts physically and functionally with a ubiquitin ligase: implications for filovirus budding.
Proc Natl Acad Sci U S A. 2000 97:13871-6.
Nakagawa S, Huibregtse JM.
Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase.
Mol Cell Biol. 2000 Nov;20(21):8244-53.
1999 |
Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP.
Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade.
Science. 1999 286:1321-6.
Beaudenon SL, Huacani MR, Wang G, McDonnell DP, Huibregtse JM.
Rsp5 ubiquitin-protein ligase mediates DNA damage-induced degradation of the large subunit of RNA polymerase II in Saccharomyces cerevisiae.
Mol Cell Biol. 1999 19:6972-9.
Wang G, Yang J, Huibregtse JM.
Functional domains of the Rsp5 ubiquitin-protein ligase.
Mol Cell Biol. 1999 19:342-52.
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