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Jon M Huibregtse

Professor, Director (Academic)
Molecular Biosciences, College of Natural Sciences


Phone: 512-232-7700

Office Location
MBB 2.312

Postal Address
AUSTIN, TX 78712

Research Summary:

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 ubiquitylation 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 current work focuses on understanding the biochemical mechanism and biological functions of ubiquitin and ubiquitin-like proteins in both mammalian and yeast cells.  Our major projects are:

1) Identification of the targets of ubiquitin ligases.  One of the major challenges in the field is characterization of the complex network of enzyme-substrate relationships in the ubiquitin system. We have recently devised an approach, based on the biochemistry of ubiquitin conjugation, that has proven to be a useful tool for identifying targets of ubiquitin ligases.  These tools are called UBAITs, for Ubiquitin Activated Interaction Traps.  UBAITs covalently ubiquitin ligases to their substrates, allowing for simple 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 ubiquitin ligases in human cells, some of which are associated with disease states, including neurologic diseases and cancer. In addition, UBAITs have utility beyond the ubiquitin system, and can be applied to almost any protein in order to characterize protein-protein interactions. 

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.  We have recently identified the cell surface receptor for ISG15 on Natural Killer cells and are characterizing its mechanism of signaling. 

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.  

Select Publications:

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.