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HUIBREGTSE, JON M

Jon M Huibregtse

Professor
Molecular Biosciences

Benjamin Clayton Centennial Professorship in Biochemistry

huibregtse@austin.utexas.edu

Phone: 512-232-7700

Office Location
MBB 2.312

Postal Address
2500 SPEEDWAY
AUSTIN, TX 78712

Research Summary:

The Huibregtse lab studies the biochemistry of the ubiquitin proteolysis system and ISG15, a ubiquitin-like modifier involved in innate immune responses to viral and microbial infections.  Our current major interests and projects include:

1) The mechanism and function of ISG15 conjugation. ISG15 is an interferon-induced ubiquitin-like protein that is conjugated to cellular proteins through a pathway separate from that for ubiquitin. ISG15 has anti-viral activity against a range of virus types, and a major goal is to understand the biochemical basis of its anti-viral activity and the mechanism of its conjugation.  One of the strongest lines of evidence indicating that ISG15 is anti-viral is that several virus types, including SARS-CoV-2 and influenza viruses, have evolved mechanisms for reversing or overcoming the effect of ISG15 conjugation.  The SARS-CoV-2 PLpro protease is a "de-ISGylase" that catalyzes deconjugation of ISG15, and PLpro also catalyzes viral polyprotein cleavage and is therefore essential for viral replication.  We have identified an FDA-approved drug that inhibits PLpro-catalyzed de-ISGylation and polyprotein cleavage and blocks CoV-2 viral replication at sub-micromolar levels.  This compound is a direct-activing antiviral that can potentially be re-purposed against COVID-19 and future emergent coronaviruses.  

2)  Remarkably, ISG15 has a second biochemical function as an extracellular signaling protein.  Free (unconjugated) ISG15 is released from cells and signals to Natural Killer cells and other cells of the immune system to release pro-inflammatory cytokines, including interferon-gamma and IL-6.  We have identified the receptor on NK cells as LFA-1, an integrin receptor. We are currently characterizing the mechanism of release of ISG15 from cells and the mechanism of ISG15-dependent cytokine secretion from NK cells. 

3)  We are very interested in the role of the ubiquitin system in protein quality control, particularly the role of co-Translational Ubiquitination (CTU).  We 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.  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 and organismal aging.  

Select Publications:

2020 Swaim, C. D., Perng, Y.-C., Zhao, X., Canadeo, L. A., Harastani, H. H., Darling, T. L.,, Boon, A. C. M., Lenschow, D. J., and Huibregtse, J. M..  6-Thioguanine Blocks SARS-CoV-2 Replication by Inhibition of PLpro. Under review.

2020 Swaim, C. D., Canadeo, L. A., Monte, K. J., Khanna, S., Lenschow, D. J., and Huibregtse, J. M.  Modulation of extracellular ISG15 signaling by pathogens and viral effector proteins.  Cell Reports 31:107772.

2020 Tomita, T., Huibregtse, J. M., and Matouschek, A.  A masked initiation region in retinoblastoma protein regulates its proteasomal degradation.  Nature Commun. 11:2019.

2020 Ryu, W. W., Stewart, R., Pectol, C., Ender, N., Wimalarathne, O., Lee, J.-H., Zanini, C. P., Harvey, A., Huibregtse, J. M., Mueller, P., and Paull, T. T.  2020.  Comprehensive identification of HSP70/HSC70 chaperone clients in human cells. PLoS Biology 18:3000606.

2018 O’Connor, H. F., Swaim, C. D., Canadeo, L. A., and Huibregtse, J. M.  Ubiquitin-Activated Interaction Traps (UBAITs):  Tools for capturing protein-protein interactions.  In The Ubiquitin Proteasome System:  Methods and Protocols.  Methods in Mol. Biol., Springer, 1844:85-100.  

2017 Swaim, C. D., Scott, A. F., Canadeo, L. A., and Huibregtse, J. M.  2017.  Extracellular ISG15 signals cytokine secretion through the LFA-1 integrin receptor.  Mol. Cell 68:581-590.  

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.