Jon M HuibregtseDirector, Professor
Institute for Cellular and Molecular Biology, Molecular Bioscienceshuibregtse@austin.utexas.edu
The University of Texas at Austin
Institute for Cellular and Molecular Biology, College of Natural Sciences
1 University Station A4800
Austin, TX 78712
The Huibregtse lab studies the biochemistry of the ubiquitin proteolysis system, a major pathway for degradation of proteins in eukaryotic cells. Our interest in this pathway arose from study of human papillomaviruses (HPVs) and their association with uterine cervical cancer, the second leading cause of cancer-related deaths among women worldwide. Characterization of the HPV E6 protein showed that it promotes cellular immortalization by stimulating the ubiquitination and degradation of p53, an important tumor suppressor protein. This has led to insights not only into how HPV-infected cells escape normal growth regulation, but also to the identification of a class of ubiquitin ligases, known as HECT ubiquitin ligases. Our work in this area now focuses on understanding the biochemical mechanism and biological functions of HECT E3s in both mammalian and yeast cells. Some of our ongoing projects are:
1) Identification of the targets of HECT E3s. We have recently devised an approach, based on the unique mechanism of HECT E3s, that covalently traps target proteins to the E3. This allows for mass spectrometry-based identification of targets simply by purificaiton of the E3 under denaturing conditions. We anticipate that this will lead to insight into the function of the many uncharacterized HECT E3s in human cells, some of which are associated with disease states, including neurologic diseases and cancer.
2) The mechanism and function of ISG15 conjugation, an interferon-induced ubiquitin-like protein (Ubl). Ubls are conjugated to cellular proteins through pathways that are parallel but distinct from those for ubiquitin, and each Ubl has its own distinct signaling functions. ISG15 is anti-viral activity against a range of virus types, and the goal of our work is to understand the biochemical basis of its anti-viral activity and the mechanism of its conjugation. We have also recently shown that ISG15 also has anti-microbial activity through a mechanism completely distinct from its intracellular conjugation function. In this context, ISG15 functions as an activator of interferon-gamma expression by acting as an extracellular signaling molecule.
3) The role of Co-Translational Ubiquitination (CTU) in protein quality control. We recently discovered that a large fraction of polyribosome-associated nascent polypeptides are ubiquitinated during translation. Based on the factors that influence the extent of CTU, our working model is that this reflects a protein quality control system that monitors protein folding during translation. Remarkably, this system can trigger the initiation of degradation of a protein before its synthesis is complete. We are exploring the potential implications of these findings in protein folding diseases and cellular aging.
2016 Canadeo, L. A., and Huibregtse, J. M. A billion ubiquitin variants to probe and modulate the UPS. Mol. Cell 62:2-4.
2016 Huibregtse, J. M., and Matouschek, A. Ramping up degradation for proliferation. Nature Cell Biology 18:141-142.
2015 O'Connor, H. F., Lyon, N. Leung, J. W., Agarwal, P., Swaim, C. D., Miller, K. M., and Huibregtse, J. M. Ubiquitin-Activated Interaction Traps (UBAITs) identify E3 ligase binding partners. EMBO Reports 12:1699-1712.
2014 Huibregtse, J. M., and Rohde, J. R. Hell's BELs: bacterial E3 ligases that exploit the eukaryotic ubiquitin machinery. PLoS Pathogens 10:e1004255.
2013 Feng, W., Durfee, L. A., and Huibregtse, J. M. 2013. Cotranslational ubiquitination mediates the degradation of newly synthesized proteins. Mol. Cell 50:368-378. view
2012 Durfee, L. A., and Huibregtse, J. M. , The ISG15 Conjugation System, Methods Mol. Biol. 832: 141-149 view
2012 Bogunovich, D., et al., Impaired IFN-gamma immunity and mycobacterial disease in humans with inherited ISG15 deficiency., Science 337: 1684-1688 view
2011 Kim, H. C., Steffen, A. M., Oldham, M. L., Chen, J., and Huibregtse, J. M. , Structure and function of a HECT domain ubiquitin binding site, EMBO Reports 12: 334-341 view
2010 Durfee, L. A., Lyon, N., Seo, K, and Huibregtse, J. M., The ISG15 conjugation system broadly targets newly synthesized proteins: implications for anti-viral function of ISG15, Mol. Cell 38: 722-732 view
2009 Kim, H. C., and Huibregtse, J. M., Polyubiquitination by HECT E3s and the determinants of chain type specificity, Mol. Cell. Biol. 29: 3307-3318 view
2008 Diao, J., Zhang, Y., Huibregtse, J. M., Zhou, D., and Chen, J., Crystal structure of SopA, a Salmonella effector protein mimicking a eukaryotic ubiquitin ligase, Nat. Struct. Mol. Biol. 15: 65-70 view
2008 Beaudenon S., Huibregtse J.M., HPV E6, E6AP and cervical cancer, BMC Biochem 21;9 Suppl 1:S4. Review view
2008 Durfee, L. A., Kelley, M. L., and Huibregtse, J. M., The basis for selective E1-E2 interactions in the ISG15 system, J. Biol. Chem. 283: 23895-902 view
2007 Ren, J., Kee, Y., Huibregtse, J.M., and Piper, R.C., Hsel, a component of the yeast Hrs-STAM uubiquitin-sorting complex, associates with ubiquitin peptidases and a ligase to contol sorting efficiency into multivesicular bodies, Mol. Biol. Cell. 18: 324-35 view
2007 Munakata, T., Liang, Y., Kim, S., McGivern, D., Huibregtse, J., Nomoto, A., and Lemon, S., Hepatitis C virus indiced, E6-AP-dependent degradation of the retinoblastoma protein, PloS Pathogens
2007 Kee, Y., and Huibregtse, J. M., Regulation of catalytic activities of HECT ubiquitin ligases, Biochem. Biophys. Res. Comm. 354: 329-333
2006 Kee, Y., Munos, W., Lyon, N., and Huibregtse, J. M. , The Deubiquitinating enzyme Ubp2 modulates Rsp5-depdnent Lys63-linked polyubiquitin conjugates in Saccharomyces cerevisiae, J. Biol. Chem. 281: 36724-36731
2006 Dastur, A., Beaudenon, S., Kelley, M., Krug, R. M., and Huibregtse, J. M., Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells, J. Biol. Chem. 281: 4334-4338
2005 Kee, Y., Lyon, N., and Huibregtse, J. M., The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme, EMBO Journal 24: 2414-2424
2005 Zhao, C., Denison, C., Huibregtse, J. M., Gygi, S., and Krug, R. M., Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways, Proc. Natl. Acad. Sci. USA 102: 10200-10205
2005 Kelley, M. L., Keiger, K. E., Lee, C. J., and Huibregtse, J. M. , The global transcriptional effects of the human papillomavirus E6 protein in cervical carcinoma cell lines are mediated by the E6AP ubiquitin ligase, J. Virol. 102: 3737-3747
2005 Liu, X., Yuan, H., Disbrow, G. L., Apolinario, T., Tomaic, V., Kelley, M. L., Baker, C. C., Huibregtse, J., and Schlegel, R., The E6AP ubiquitin ligase is required for transactivation of the hTERT promoter by the human papillomavirus E6 oncoprotein, J. Biol. Chem. 280: 10807-10816
2004 Salvat, C. Wang, G., Dastur, A., Lyon, N., and Huibregtse, J.M., The -4 phenylalanine is required for substrate ubiquitination catalyzed by HECT ubiquitin ligases., J. Biol. Chem. 279: 18935-18943
2004 Zhao, C. Beaudenon, S.L., Kelley, M.L., Waddell, M.B., Yuan, W., Schulman, B.A., Huibregtse, J.M., and Krug, R.M., The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, and IFN-alpha/beta-induced ubiquitin-like protein, Proc. Natl. Acad. Sci. U.S.A. 101: 7578-7582
Bio 336/394M, Tumor Biology. Undergraduate and Graduate sections taught concurrently, Fall semester only.