Curriculum Vitae Yihong Ye, Ph.D. ______Laboratory of Molecular Biology National Institute of Diabetes & Digestive & Kidney Diseases National Institutes of Health 5 Center Drive, Building 5, Room 433 Bethesda, MD 20892 Phone: (301) 5940845 Fax: (301) 4960201 e-mail: [email protected]

Education Ph.D., University of Pennsylvania, Philadelphia, PA, 2000 B.S., Peking University, School of Medicine, Beijing, China 1995

Research Chronology 2011-present Senior Investigator National Institute of Diabetes & Digestive & Kidney Diseases National Institutes of Health

2005-2011 Tenure track investigator National Institute of Diabetes & Digestive & Kidney Diseases National Institutes of Health

2000-2005 Postdoctoral fellow Department of Cell Biology Harvard Medical School

Honors and Awards The NIH intramural AIDS Targeted Antiviral Program (IATAP) Award (2009-2015) $92,000/year

Co-inventor, Imidazolidinone compounds, methods to inhibit deubiquitination and methods of treatment (pending)

Co-inventor, Hydrazone and diacyl hydrazine compounds and methods of use, initial filing in 2010

Helen Hay Whitney postdoctoral fellowship, 2001-2004

Leukemia & Lymphoma society fellowship, 2001 (award declined)

Finalist, the Larry Sandler award, 42nd Annual Drosophila Research Conference, Washington D.C., 2001

Saul Weingrad thesis award, University of Pennsylvania, 2001

1 Juan Graña graduate teaching assistantship, University of Pennsylvania, 1999

Professional activities  Co-organizer of the “ synthesis and degradation’ theme for the 2016 ASBMB annual meeting.  Editorial board member; Scientific Reports, 2014-; Frontiers Molecular Biosciences, 2014-; Journal of Biological Chemistry, 2015-  NIH Loan Repayment Program reviewing committee, 2014  Co-chair of the Earl Stadtman Investigator Search Committee, Cell Biology & Cell Signaling, 2013 and 2014  Earl Stadtman Investigator Search Committee, Cell Biology & Cell Signaling, 2012  Nancy Nossal Fellowship Reviewing Committee, 2012-2014  Organizer, the protein trafficking interest group, NIH 2011-2015  Organizer, the Laboratory of Molecular Biology Research Symposium, St. Michael, MD, 2007  Judge for the NIH research festival, 2006  Ad hoc grant reviewer for the National Science Foundation, the Israeli Science Foundation, the Marsden Fund New Zealand  Ad hoc reviewer for Cell, Mol. Cell, JCB, EMBO, EMBO reports, Cell Reports, Nat. Cell Biol., Nat. Commun., Nat. Struct. and Mol. Biol., & Dev., PNAS, MCB, MBC, JBC, PLoS One, Biochem. J.  Teaching assistant, University of Pennsylvania, 1999  Member of the American Society of Cell Biology (ASCB)  Member of the American Society of Biochemistry and Molecular Biology (ASBMB)  Member of the Society of Chinese Bioscientists in America (SCBA)

Bibliography First author and corresponding author research articles 1. Lee, J.G., Takahama, S., Zhang, G., Tomarev, S., Ye, Y. (2015) Unconventional secretion of misfolded adapts cells to proteasome dysfunction in mammalian cells. under review at Nat. Cell Biol.

2. Zhang, T., Xu, Y., Liu, Y., Ye, Y. (2015) gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum. Mol. Biol. Cell, in press.

2 3. Liu, Y., Soetandyo, N., Lee, J.G., Liu, L., Xu, Y., Clemons, W.M. Jr., Ye, Y. (2014) USP13 antagonizes gp78 to maintain functionality of a in ER-associated degradation. eLIFE, 3:e01369. doi: 10.7554.

4. Liu, W., Shang, Y., Zeng, Y., Liu, C., Li, Y., Zhai, L., Wang, P., Lou, J., Xu, P., Ye, Y.*, Li, W.* (2014) Dimeric Ube2g2 simultaneously engages donor and acceptor to form Lys48-linked chains. EMBO J. 33:46-61

5. Huang, C.H., Chu, Y.R., Ye, Y.*, Chen, X.* (2014) Role of HERP and a HERP-related protein in HRD1-dependent protein degradation at the endoplasmic reticulum. J. Biol. Chem. 289(7): 4444-4454.

6. Lee, J.G., Kim, W., Gygi, S., Ye, Y. (2013) Characterization of the deubiquitinating activity of USP19 and its role in endoplasmic reticulum-associated degradation. J. Biol. Chem. 288(35): 25330-25339.

7. Xu, Y., Liu, Y., Lee, J.G., Ye, Y. (2013) A ubiquitin-like domain recruits an oligomeric chaperone to a retrotranslocation complex in the ER membrane. J. Biol. Chem. 288(25):18068-18076.

8. Lee, J.-G., Soetandyo, N., Baek, K., Ye, Y. (2013) Reversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells. Nature Communications, 4:1568. doi: 10.1038/ncomms2532.

9. Ramanathan, H.N., Zhang, G., Ye, Y. (2013) Monoubiquitination of EEA1 regulates endosome fusion and trafficking. Cell & Bioscience, 3(1):24. doi: 10.1186/2045-3701-3- 24.

10. Xu, Y., Cai, M., Yang, Y., Huang, L., Ye, Y. (2012) SGTA recognizes a non-canonical ubiquitin-like domain in the Bag6-Ubl4A-Trc35 complex to promote ER-associated degradation. Cell Reports 2: 1633-1644.

11. Ramanathan H. N., Ye, Y. (2012) The p97 ATPase associates with EEA1 to regulate the size of early endosomes. Cell Research 22: 346-359.

12. Wang, Q., Liu, Y., Soetandyo, N., Baek, K., Ramanujan, H., Ye, Y. (2011) A -associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation. Molecular Cell 42: 758-770.

13. Wang, Q., Shinkre, B., Lee, J.-G., Liu, Y., Weniger, M., Chen, W., Wiestner, A., Trenkle, W.C., Ye, Y. (2010) The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group. PloS ONE, 5:e15479.

14. Soetandyo, N., Ye, Y. (2010) The p97 ATPase dislocates MHC class I heavy chain in US2 expressing cells via an Ufd1-Npl4 independent mechanism. J. Biol. Chem., 285: 32352-32359.

15. Soetandyo, N., Wang, Q., Ye., Y.*, Li, L.* (2010) Role of intramembrane charged residues in the quality control of unassembled T-cell receptor  chain at the endoplasmic reticulum. J. Cell Sci. 123:1031-1038.

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16. Li, W., Tu, D., Li, L., Wollert, T., Ghirlando, R., Brunger, A.T.*, Ye, Y.* (2009) Mechanistic insights into active site-associated polyubiquitination by the ubiquitin conjugating enzyme Ube2g2. Proc. Natl. Acad. Sci. USA. 106, 3722-3727.

17. Wang, Q., Mora-Jensen, H., Weniger, M.A., Perez-Galan, G., Wolford, C., Hai, T., Ron, D., Chen, W., Trenkle, W., Wiestner, A.*, Ye, Y.* (2009) ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3 only protein NOXA in cancer cells. Proc. Natl. Acad. Sci. USA. 106, 2200-2205.

18. Li, L., Soetandyo, N., Wang, Q., and Ye, Y. (2009) The zinc finger protein A20 targets TRAF2 to the lysosomes for degradation. BBA Mol. Cell Res. 1793, 346-353.

19. Wang, Q., Li, L., and Ye, Y. (2008) Inhibition of p97-dependent protein degradation by Eeyarestatin I. J. Biol. Chem. 283, 7445-7454.

20. Li, L., Hailey, D., Soetandyo, N., Li, W., Lippincott-Schwartz, J., Shu, H-B., and Ye, Y. (2008) Localization of A20 to a lysosome-associated compartment and its role in NFB signaling. BBA Mol. Cell Res. 1783, 1140-1149.

21. Li, W., Tu, D., Brunger, A.T., and Ye, Y. (2007) A ubiquitin ligase transfers preformed polyubiquitin chains from a conjugating enzyme to a substrate. Nature 446, 333-337.

22. Wang, Q., Li, L., and Ye, Y. (2006) Regulation of retro-translocation by p97-associated ataxin-3. J. Cell Biol. 174, 963-971.

23. Ye, Y., Shibata, Y., Kikkert, M., Voorden, S., Weirdz, E., and Rapoport, T.A. (2005) Recruitment of the p97 ATPase and ubiquitin ligases to the site of retro-translocation at the ER membrane. Proc. Natl. Acad. Sci. USA. 102, 14132-14138.

24. Ye, Y., Shibata, Y., Yun, C., Ron, D., and Rapoport, T.A. (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429, 841-847.

25. Ye, Y., Meyer, H.H., and Rapoport, T.A. (2003) Function of the p97-Ufd1-Npl4 complex in retro-translocation from the ER to the cytosol: dual recognition of non-ubiquitinated polypeptide segments and poly-ubiquitin chains. J. Cell Biol. 162, 71-84.

26. Ye, Y., Meyer, H., and Rapoport, T.A. (2001) The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414, 652-656.

27. Ye, Y., and Fortini, M. E. (1999) Apoptotic activity of wild-type and Alzheimer's disease-related mutant Presenilins in Drosophila. J. Cell Biol. 146, 1351-1364.

28. Ye, Y., Lukinova, N., and Fortini, M. E. (1999) Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398, 525-529.

29. Ye, Y., and Fortini, M.E. (1998) Characterization of Drosophila Presenilin and its colocalization with Notch during development. Mech. Dev. 79, 199-211.

Research articles (from collaboration)

4 30. Yan, L., Liu, W., Zhang, H., Liu, C., Shang, Y., Ye, Y., Zhang, X., Li, W. (2014) Ube2g2-gp78-mediated HERP polyubiquitination is involved in ER stress recovery. J. Cell Sci. 127: 1417-1427.

31. Huang, C.H., Hsiao, H.T., Chu, Y.R., Ye, Y. and Chen, X. (2013) Derlin2 protein facilitates HRD1-mediated retro-translocation of sonic hedgehog at the endoplasmic reticulum. J. Biol. Chem. 288:25330-25339.

32. Nery, F.C., Armata1, I.A., Farley, J.E., Cho, J.A., Yaqub, U., Chen, P., da Hora, C., Wang, W., Tagaya, M., Klein, C., Tannous, B., Caldwell K.A., Caldwell, G.A., Lencer, W.I., Ye, Y., Breakefield, X.O. (2011) TorsinA participates in endoplasmic reticulum- associated degradation. Nature Communications 2: 393. doi: 10.1038/ncomms1383.

33. Zhong, Y., Wang, Y., Yang, H., Ballar, P., Lee, J.G., Ye, Y., Monteiro M.J., Fang, S. Importinβ interacts with the ER-associated degradation machinery and promotes ubiquitination and degradation of mutant -antitrypsin. J Biol Chem. 2011 286: 33921- 33930.

34. Hübener, L., Vauti, F. Funke, C., Wolburg, H., Ye. Y., Schmidt, T., Wolburg-Buchholz, K., Schmitt, I., Gardyan, A., Brieβen, S., Arnold, H., Nguyen, H. Riess., O. (2011) N- terminal ataxin-3 causes neurological symptoms with inclusions, endoplasmic reticulum stress and ribosomal dislocation. Brain 134:1925-1942.

35. Weniger, M.A., Rizzatti, E.G., Pérez-Galán, P., Liu, D., Wang, Q., Munson, P.J., Raghavachari, N., White, T., Tweito, M.M., Dunleavy, K., Ye, Y., Wilson, W., Wiestner, A. (2011) Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma. Clin Cancer Res. 17:5101-5112.

36. Magadan, H., Perez-victoria, P., Ye, Y., Klaus, S., Bonifacino, J. (2010) Multilayered Mechanism of CD4 Downregulation by HIV-1 Vpu Involving Distinct ER Retention and ERAD Targeting Steps PLOS Pathogen e1000869.

37. Bernardi, K.M., Williams, J.M., Kikkert, M., Van Voorden, S., Wiertz, E..J, Ye, Y., Tsai, B. (2009) The E3 ubiquitin ligases Hrd1 and gp78 bind to and promote cholera toxin retro- translocation. Mol Biol Cell. 21, 140-151.

38. Lim, P.J., Danner, R., Liang, J., Doong, H., Harman, C., Srinivasan, D., Rothenberg, C., Wang, H., Ye, Y., Fang, S., Monteiro, M.J. (2009) Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD. J. Cell Biol. 187, 201-217.

39. Tu, D., Li, W., Ye, Y., and Brunger, A.T. (2007) Structure and function of the Yeast U- box containing ubiquitin ligase Ufd2p. Proc. Natl. Acad. Sci. USA. 104:15599-15606.

40. Lu, Y., Lv, Y., Ye, Y., Wang, Y., Hong, Y., Fortini, M.E., Zhong, Y., and Xie, Z. (2007) A role for presenilin in post-stress regulation: effects of presenilin mutants on Ca2+ currents in Drosophila. FASEB J. 21:2368-2378.

41. Seidner, G.A., Ye, Y., Faraday, M.M., Alvord, W.G., and Fortini, M.E. (2006) Modeling clinically heterogeneous Presenilin mutations with transgenic Drosophila. Current Biol. 16, 1126-1133.

5 42. Wang, X., Ye, Y., Lencer, W., and Hansen, T.H. (2006) The viral E3 ubiquitin ligase mK3 uses the Derlin/p97 ERAD pathway to mediate downregulation of MHC-I proteins. J. Biol. Chem. 281, 8636-8644.

43. Kothe, M., Ye, Y., Wagner, J.S., Rapoport, T.A., and Lencer, W.I. (2005) Role of p97 AAA-ATPase in the retro-translocation of the cholera toxin A1 chain - a non-ubiquitinated substrate. J. Biol. Chem. 280, 28127-28132.

44. Flierman, D., Ye, Y., Dai, M., Chau, V., and Rapoport, T.A. (2003) Poly-ubiquitin serves as a recognition signal, rather than a ratcheting molecule, during retro-translocation of proteins across the ER Membrane. J. Biol. Chem. 278, 34774-34782.

45. Hu, Y., Ye, Y., and Fortini, M.E. (2002) Nicastrin is required for -secretase cleavage of the Drosophila Notch receptor. Developmental Cell 2, 69-78.

46. Duan, D., Sharma, P., Dudus, L., Zhang, Y., Sanlioglu, S., Yan, Z., Yue, Y., Ye, Y., Lester, R., Yang, J., Fisher, K.J., Engelhardt, J. F. (1999) Formation of adeno-associated virus circular genomes is differentially regulated by adenovirus E4 ORF6 and E2a expression. J. Virol. 73, 161-169.

47. Chang, W.-P., Ye, Y., and Clevenger, C.V. (1998) Stoichiometric structure-function analysis of the prolactin receptor signaling domain by receptor chimeras. Mol. Cell. Biol. 18, 896-905.

Invited reviews and commentaries 1. Xia, D. and Ye, Y. (2015) In search of a cure for proteostasis-addicted tumors: A AAA target revealed. Cancer Cell, in press

2. Christianson, J.C. and Ye, Y. (2014) Cleaning up in the endoplasmic reticulum: ubiquitin in charge. Nat. Struct. & Mol. Biol., 21: 325-335.

3. Zhang, T. and Ye, Y. (2014) The final moments of misfolded proteins en route to the proteasome. DNA & Cell Biology, 33(8):477-483.

4. Lee, J. and Ye, Y. (2013) Bag6/Bat3/Scythe: A novel chaperone activity with diverse regulatory functions in protein biogenesis and degradation. BioEssays, 35:377-385.

5. Liu, Y. and Ye, Y. (2012) The roles of p97-associated deubiquitinases in protein quality control at the endoplasmic reticulum. Current Protein & Peptide Science 13: 436-446.

6. Ramanathan, H. and Ye, Y. (2011) Revoking the cellular license to replicate-yet another AAA assignment. Mol. Cell, 44, 3-4.

7. Ramanathan, H. and Ye, Y. (2011) Cellular strategies for making mono-ubiquitin signals. Critical Reviews in Biochemistry and Molecular Biology, 47: 17-28.

8. Liu, Y. and Ye, Y. (2011) Proteostasis regulation at the endoplasmic reticulum: a new site of perturbation for targeted cancer therapy. Cell Research 21, 867-883.

9. Ye, Y.* and Rape, M.* (2009) Building polyubiquitin chains: E2 at work. Nat. Rev. Mol. Cell Biol. 11, 755-764.

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10. Li, W. and Ye, Y. (2008) Polyubiquitin chains: functions, structures, and mechanisms. Cell. Mol. Life Sci. 65, 2397-2406.

11. Ye, Y. (2006) Diverse functions with a common regulator: ubiquitin takes command of an AAA ATPase. J. Struct. Biol., 156, 29-40.

12. Ye, Y. (2005) The role of the ubiquitin proteasome system in ER quality control. Essay in Biochemistry. 41, 99-122.

13. Tsai, B., Ye, Y., and Rapoport, T.A. (2002) Retrotranslocation of proteins from the endoplasmic reticulum into cytosol. Nat. Rev. Mol. Cell Biol. 3, 246-256.

14. Ye, Y. and Fortini, M. E. (2000) Proteolysis and intracellular signaling. Sem. Cell Dev. Biol. 11, 211-221.

15. Ye, Y., Lukinova, N., and Fortini, M.E. (2000) Functional studies of Presenilin in Notch signaling. Res Pract Alz Dis. 3, 41-50.

* co-corresponding authorship

Invited Presentations (2004-2014) 10/2015 University of Minnesota, Minneapolis, MN 11/2014 Peking University, School of Medicine, Beijing, China 11/2014 Institute of Zoology, Chinese Academy of Sciences, Beijing, China 11/2014 Institute of Biophysics, Chinese Academy of Sciences, Beijing, China 10/2014 Yangzhou University, Yangzhou, China 02/2014 National Cancer Institute, Frederick, MD, invitation accepted 11/2013 SCBA technology workshop on genome editing, NIH, Bethesda, MD 11/2013 Uniformed Services University of Health Sciences, Bethesda, MD 11/2013 Johns Hopkins University, Baltimore, MD 10/2013 University of Colorado Boulder, Boulder CO 09/2013 EMBO workshop “AAA+ Proteins-from mechanism and disease to targets”. Neuss, Germany, invitation accepted 06/2013 The 18th CBA Annual Conference, Rockville, Maryland 06/2013 FASEB Summer Research Conference “From Unfolded Proteins in the Endoplasmic Reticulum to Diseases”, Saxtons River, VT 06/2013 Academia Sinica, Taipei, Taiwan 06/2013 National Health Research Institutes, Miaoli, Taiwan 04/2013 NIH Director’s seminar series, Bethesda, MD 03/2013 National Cancer Institute, NIH, Bethesda, MD 09/2012 National Institute of Child Health and Human Development, NIH, Bethesda MD 09/2012 Cornell University, Ithaca, NY 06/2012 FASEB Summer Research Conference “Ubiquitin & Cellular Regulation”, Saxtons River, VT 03/2012 Gordon Research Conference “Protein Transport across the membranes” 03/2012 University of Texas Health Science Center at San Antonio, TX 01/2012 The 2nd Proteomics of Protein Degradation and Ubiquitin Pathways conference, San Diego, CA 01/2012 University of California, Irvine, CA

7 11/2011 Iowa State University, Ames, IA 11/2011 University of Delaware, Newark, DE 06/2011 FASEB Summer Research Conference “From Unfolded Proteins in the Endoplasmic Reticulum to Diseases”, Saxtons River, VT 05/2011 Cold Spring Harbor Ubiquitin Family meeting, New York, NY 05/2011 Academia Sinica, Taipei, Taiwan 04/2011 National Health Research Institutes, Miaoli, Taiwan 04/2011 Institute of Zoology, Chinese Academy of Science, Beijing, China 03/2011 Thomas Jefferson University, Philadelphia, PA 01/2011 SUNY Upstate Medical University, Syracuse, NY 12/2010 Johns Hopkins University, Baltimore, MD 03/2010 National Cancer Institute, Bethesda, MD 03/2010 New York University, New York, NY 11/2009 The Catholic University of America, Washington, DC 07/2009 the 8th International Conference on AAA proteins, Toronto, Canada 07/2009 Beijing Normal University, Beijing, China 07/2009 Institute of Biochemistry & Cell Biology, Shanghai, China 07/2009 the University of Science & Technology, Hefei, China 06/2009 National Institute of Biological Science, Beijing, China 06/2009 BIT Life Sciences'2nd Annual World Cancer Congress, Beijing, China 06/2009 FASEB Summer Research Conference “From Unfolded Proteins in the Endoplasmic Reticulum to Diseases”, Saxtons River, VT 04/2009 The Ubiquitin Family Conference, Cold Spring Harbor, NY 02/2009 Molecular Targets for Cancer Prevention Conference, Bethesda, MD 01/2009 Protein Misfolding and Misprocessing in Disease Conference, Bethesda, MD 03/2008 Millennium Pharmaceuticals Inc., Boston, MA 05/2008 Laboratory of Cell and Developmental Biology, NIDDK, National Institutes of Health, Bethesda, MD 08/2007 FASEB Summer Research Conference “From Unfolded Proteins in the Endoplasmic Reticulum to Diseases”, Indian Wells, CA 06/2007 Marie Curie Symposium “The ubiquitin-proteasome system in cardiovascular disease”, Hamburg, Germany 06/2007 Centre for Molecular Neurobiology, University Clinic Hamburg Eppendorf, Hamburg, Germany 04/2007 Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 04/2007 The Ubiquitin Family Conference, Cold Spring Harbor, NY 12/2006 Department of Cellular & Molecular Physiology, Pennsylvania State University Medical Center, Hershey, PA 03/2006 Cell Biology and Metabolism Program, NICHD, NIH, Bethesda, MD 07/2005 Medical Biotechnology Center, University of Maryland, MD 06/2005 Gordon Research Conference-protein transport across cell membranes. Colby-sawyer College, NH 04/2005 ECFS Conference-New Frontiers in Basic Science of Cystic Fibrosis. Évora, Portuga 12/2004 Institute of Neuroscience, Chinese Academy of Science, Shanghai, China 09/2004 Joint 59th Harden/EMBO conference: The ubiquitin-proteasome system in health and disease. Cirencester, UK 09/2004 MRC Laboratory for Molecular Cell Biology & Cell Biology, University College London, London, UK

8 03/2004 University of California at San Francisco, San Francisco, CA 02/2004 Harvard University, Cambridge, MA 02/2004 Duke University, Durham, NC 02/2004 University of California at San Diego, San Diego, CA 01/2004 University of Chicago, Chicago, IL 01/2004 Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, MD

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