Update Your ProfileAcademic Title:
Professor
Primary Appointment:
Pharmacology & Physiology
Secondary Appointment(s):
BioChemistry&Molecular Biology
Email:
Location:
111 S Penn St
Phone (Primary):
(410) 706-2220
Fax:
(410) 706-8184
Education and Training
MBBS, Clinical Medicine, Anhui Medical University, Anhui, China
Postdoctoral Associate, Physiology, University of Iowa, Iowa City, IA
PhD, Anatomy and Cell Biology, University of Iowa, Iowa City, IA
Postdoctoral Fellow, National Cancer Institute, Bethesda, MD
Biosketch
Dr. Fang is an accomplished expert in the field of the ubiquitin-proteasome system and the ER-associated degradation (ERAD) pathway. He is also deeply interested in understanding how ERAD dysfunction and the unfolded protein response (UPR) contribute to disease pathogenesis.
In recent years, Dr. Fang has re-focused his research on drug discovery through targeting the regulation of ER proteostasis, in collaboration with scientists at the National Center for Advancing Translational Sciences (NCATS). Currently, his lab is working on several small molecules, for examples, the first small molecule UBA1 activity enhancer and the first small molecule RNF5 inhibitor and degrader, that show great potential to be developed into first-in-class drugs. These drugs could help treat a wide range of disorders, including VEXAS syndrome, spinal muscular atrophy, α-1-antitrypsin deficiency-associated liver disease, obesity, obesity-related cancer, as well as aging and age-related diseases.
Research/Clinical Keywords
Proteostasis, UBA1 activity enhancers, RNF5 inhibitor and degrader, drug discovery, ubiquitination, ERAD, unfolded protein response, ER-phagy, VEXAS syndrome, spinal muscular atrophy, α-1-antitrypsin deficiency-associated liver disease, obesity-related cancer, aging, and age-related diseases.
Highlighted Publications
Ruan J, Liang D, Yan W, Zhong Y, Talley DC, Rai G, Tao D, LeClair CA, Simeonov A, Zhang Y, Chen F, Quinney NL, Boyles SE, Cholon DM, Gentzsch M, Henderson MJ, Xue F, Fang S. A small-molecule inhibitor and degrader of the RNF5 ubiquitin ligase. Mol Biol Cell. 2022 Nov 1;33(13):ar120. PMCID: PMC9634977
Zhong Y, Yan W, Ruan J, Fang M, Yu C, Du S, Rai G, Tao D, Henderson MJ, Fang S. XBP1 variant 1 promotes mitosis of cancer cells involving upregulation of the polyglutamylase TTLL6. Hum Mol Genet. 2022 Aug 17;31(15):2639-2654. PMCID: PMC9396943
Yan W, Zhong Y, Hu X, Xu T, Zhang Y, Kales S, Qu Y, Talley D, Baljinnyam B, LeCalir C, Simeonov A, Polster B, Huang R, Ye Y, Rai G, Henderson M, Tao D, Fang S. Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes. Nat Commun 2023 Aug 9;14(1):4798. doi: 10.1038/s41467-023-40537-x. PMCID: PMC10412574
Zhong Y, Wang J, Henderson MJ, Yang P, Hagen BM, Siddique T, Vogel BE, Deng HX, Fang S. Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus. eLife. 2017 May 2;6. pii: e23759. PMCID: PMC5449186
Liu Y, Gu Y, Chen Y, Wang X, Zhou G, Li J, Wang M*, Fang S*, Yang Y*. Translocational attenuation mediated by thePERK-SRP14 axis is a protective mechanism of unfolded protein response.Cell Rep. 2024 Jun 27;43(7):114402. doi: 10.1016/j.celrep.2024.114402. Online ahead of print.PMID:38943644
Additional Publication Citations
Feng L, Zhang J, Zhu N, Ding Q, Zhang X, Yu J, Qiang W, Zhang Z, Ma Y, Huang D, Shen Y, Fang S, Yu Y, Wang H, Shen Y. Ubiquitin ligase SYVN1/HRD1 facilitates degradation of the SERPINA1 Z variant/α-1-antitrypsin Z variant via SQSTM1/p62-dependent selective autophagy. Autophagy. 2017 Apr 3;13(4):686-702. PMCID: PMC5388218
Sun J, Wang D, Guo L, Fang S, Wang Y, Xing R. Androgen Receptor Regulates the Growth of Neuroblastoma Cells in vitro and in vivo. Front Neurosci. 2017 Mar 7;11:116. PMCID: PMC5339338
Bao D, Cheng C, Lan X, Xing R, Chen Z, Zhao H, Sun J, Wang Y, Niu C, Zhang B, Fang S. Regulation of p53wt glioma cell proliferation by androgen receptor-mediated inhibition of small VCP/p97-interacting protein expression. Oncotarget. 2017 Apr 4;8(14):23142-23154. PMCID: PMC5410292
Wu T, Chen W, Zhong Y, Hou X, Fang S, Liu CY, Wang G, Yu T, Huang YY, Ouyang X, Li HQ, Cui L, Yang Y. Nuclear Export of Ubiquitinated Proteins Determines the Sensitivity of Colorectal Cancer to Proteasome Inhibitor. Mol Cancer Ther. 2017 Apr;16(4):717-728.
Chen Q, Zhong Y, Wu Y, Liu L, Wang P, Liu R, Cui F, Li Q, Yang X, Fang S, Xie Q. HRD1-mediated ERAD tuning of ER-bound E2 is conserved between plants and mammals. Nat Plants. 2016 Jun 20;2:16094.
Liu L, Liu C, Zhong Y, Apostolou A, Fang S. ER stress response during the differentiation of H9 cells induced by retinoic acid. Biochem Biophys Res Commun. 2012 Jan 13;417(2):738-43.
Liu A, Gong P, Hyun SW, Wang KZ, Cates EA, Perkins D, Bannerman DD, Puché AC, Toshchakov VY, Fang S, Auron PE, Vogel SN, Goldblum SE. TRAF6 Protein Couples Toll-like Receptor 4 Signaling to Src Family Kinase Activation and Opening of Paracellular Pathway in Human Lung Microvascular Endothelia. J Biol Chem. 2012 May 11;287(20):16132-45. Epub 2012 Mar 23. PMCID: PMC3351307
Xu M, Chen G, Fu W, Liao M, Frank JA, Bower KA, Fang S, Zhang Z, Shi X, Luo J. Ethanol disrupts vascular endothelial barrier: implication in cancer metastasis. Toxicol Sci. 2012 May;127(1):42-53. PMCID: PMC3327869
Chen Z, Du S, Fang S. gp78: a multifaceted ubiquitin ligase that integrates a unique protein degradation pathway from the endoplasmic reticulum. Curr Protein Pept Sci. 2012 Aug 1;13(5):414-24.
Shen YX, Sun AM, Fang S, Feng LJ, Li Q, Hou HL, Liu C, Wang HP, Shen JL, Luo J, Zhou JN. Hrd1 facilitates tau degradation and promotes neuron survival. Curr Mol Med. 2012 Feb 1;12(2):138-52.
Zhong Y, Wang Y, Yang H, Ballar P, Lee JG, Ye Y, Monteiro MJ, Fang S. Importin β interacts with the ER-associated degradation machinery and promotes ubiquitination and degradation of mutant {alpha}1-antitrypsin. J Biol Chem. 2011 Sep 30;286(39):33921-30. PMCID: PMC3190800
Wang Y, Ballar P, Zhong Y, Zhang X, Liu C, Zhang YJ, Monteiro MJ, Li J, Fang S. SVIP Induces Localization of p97/VCP to the Plasma and Lysosomal Membranes and Regulates Autophagy. PLoS One. 2011;6(8):e24478. Epub 2011 Aug 31. PMCID: PMC3164199
Ugolino J, Fang S, Kubisch C, Monteiro MJ. Mutant Atp13a2 proteins involved in parkinsonism are degraded by ER-associated degradation and sensitize cells to ER-stress induced cell death. Hum Mol Genet. 2011 Sep 15;20(18):3565-77. Epub 2011 Jun 10. PMCID: PMC3159557
Dong G, Ferguson JM, Duling AJ, Nicholas RG, Zhang D, Rezvani K, Fang S, Monteiro MJ, Li S, Li XJ, Wang H. Modeling pathogenesis of Huntington's disease with inducible neuroprogenitor cells. Cell Mol Neurobiol. 2011 Jul;31(5):737-47. doi: 10.1007/s10571-011-9679-0. Epub 2011 Mar 31.
Ke Z, Wang X, Liu Y, Fan Z, Chen G, Xu M, Bower KA, Frank JA, Li M, Fang S, Shi X, Luo J. Ethanol Induces Endoplasmic Reticulum Stress in the Developing Brain. Alcohol Clin Exp Res. 2011 Sep;35(9):1574-1583. doi: 10.1111/j.1530-0277.2011.01503.x. Epub 2011 May 20.
Xu S, Peng G, Wang Y, Fang S, Karbowski M. The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover. Mol Biol Cell. 2010 Dec 14. [Epub ahead of print]. PMCID: PMC3031461
Jiang H, Jans R, Xu W, Rorke EA, Lin CY, Chen YW, Fang S, Zhong Y, Eckert RL. Type I transglutaminase accumulation in the endoplasmic reticulum may be an underlying cause of autosomal recessive congenital ichthyosis. J Biol Chem. 2010 Oct 8;285(41):31634-46. PMCID: PMC2951236
Rothenberg C, Srinivasan D, Mah L, Kaushik S, Peterhoff CM, Ugolino J, Fang S, Cuervo AM, Nixon RA, Monteiro MJ. Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy. Hum Mol Genet. 2010 Aug 15;19(16):3219-32. PMCID: PMC2908472
Airavaara M, Chiocco MJ, Howard DB, Zuchowski KL, Peränen J, Liu C, Fang S, Hoffer BJ, Wang Y, Harvey BK. Widespread cortical expression of MANF by AAV serotype 7: localization and protection against ischemic brain injury. Exp Neurol. 2010 Sep;225(1):104-13. PMCID: PMC2925275
Yang H, Liu C, Zhong Y, Luo S, Monteiro MJ, Fang S (2010). Huntingtin Interacts with the Cue Domain of gp78 and Inhibits gp78 Binding to Ubiquitin and p97/VCP. Plos One, Jan 26, 5(1):e8905. PMCID: PMC2811200
Ballar P, Ors AU, Yang H, Fang, S. Differential regulation of CFTRDeltaF508 degradation by ubiquitin ligases gp78 and Hrd1. Int J Biochem Cell Biol. 2010, 42(1):167-73.
Yu YQ, Liu LC, Wang FC, Liang Y, Cha DQ, Zhang JJ, Shen YJ, Wang HP, Fang, S., Shen YX. Induction profile of MANF/ARMET by cerebral ischemia and its implication for neuron protection. J Cereb Blood Flow Metab. 2010 Jan;30(1):79-91. PMCID: PMC2949098
Lim PJ, Danner R, Liang J, Doong H, Harman C, Srinivasan D, Rothenberg C, Wang H, Ye Y, Fang, S., Monteiro MJ. Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD. J Cell Biol. 2009 Oct 19;187(2):201-17. PMCID: PMC2768832
Herr RA, Harris J, Fang, S., Wang X, Hansen TH. Role of the RING-CH Domain of Viral Ligase mK3 in Ubiquitination of Non-Lysine and Lysine MHC I Residues. Traffic. 2009 Sep;10(9):1301-17.
Xu K, Shimelis H, Linn DE, Jiang R, Yang X, Sun F, Guo Z, Chen H, Wei Li, Chen HG, Kong X, Melamed J, Fang, S., Zhen Xiao, Veenstra TD and Qiu Y. Regulation of androgen receptor transcriptional activity and specificity by RNF6. Cancer Cell. 15(4):270-82. PMCID: PMC2848969
Ballar P, Fang, S. Regulation of ER-associated degradation via p97/VCP-interacting motif. Biochem Soc Trans. 2008 Oct;36(Pt 5):818-22.
Apostolou A, Shen Y, Liang Y, Luo J, Fang, S. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp Cell Res. 2008 Aug 1;314(13):2454-67.
Ballar, P. Zhong, Y. Nagahama, M. Tagaya, M. Shen, Y. Fang, S. (2007). SVIP is an endogenous inhibitor of ER-associated degradation. J Biol Chem. 282(47):33908-14
Yang H, Zhong X, Ballar P, Luo S, Shen Y, Rubinsztein DC, Monteiro MJ, Fang S (2007). Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin. Exp Cell Res. 313(3):538-50.
Shen Y, Ballar P, Apostolou A, Doong H, Fang, S. (2007). ER stress differentially regulates the stabilities of ERAD ubiquitin ligases and their substrates. Biochem Biophys Res Commun. 352(4):919-24.
Ballar P, Shen Y, Yang H, Fang, S. (2006). The role of a novel p97/valosin-containing protein-interacting motif of gp78 in endoplasmic reticulum-associated degradation. J Biol Chem. 281(46):35359-68.
Shen Y, Ballar P, Fang, S. (2006). Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of alpha-1-antitrypsin. Biochem Biophys Res Commun. 349(4):1285-93.
Zhang J, Jiang Y, Jia Z, Li Q, Gong W, Wang L, Wei D, Yao J, Fang, S., Xie K (2006). Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 23(7-8):401-10.
Lu ZM, Jia YS, Wang SH, Fang, S., and Wu Q (2006). Significance of an ubiquitin ligase hHRD1 expressed in human breast carcinoma. Acta Anatomica Sinica. 37(6): 681-4.
Liang, J., Yin, C., Doong, H., Fang, S., Peterhoff, C., Nixon, R.A., and Monteiro, M.J. (2006). Characterization of Erasin: A novel endoplasmic reticulum protein involved in promoting endoplasmic reticulum-associated protein degradation. J Cell Sci 119(Pt 19): 4011-24
Vij N, Fang, S., Zeitlin PL (2006) Selective inhibition of ERAD rescues uF508-CFTR and suppresses IL8 levels: therapeutic implications. J Biol Chem. 281(25):17369-78
Gong W, Jiang Y, Wang L, Wei D, Yao J, Huang S, Fang, S., Xie K (2005). Expression of autocrine motility factor correlates with the angiogenic phenotype of and poor prognosis for human gastric cancer. Clin Cancer Res. 11(16):5778-83.
Zhong, X., Shen, Y.X., Ballar, P., Apostolou, Agami, R., and Fang, S. (2004). AAA ATPase p97/VCP interacts with gp78, a ubiquitin ligase for ER-associated degradation. J Biol Chem 279: 45676-84
Davydov, I.V., Woods, D., Safiran, J.S., Oberoi1, P., Fearnhead, H.O., Fang, S., Jensen, J., Weissman, A.M., Kenten, J. and Vousden, K.H. (2004). Assay for ubiquitin ligase activity: high throughput screen for inhibitors of hdm2. J Biomol Screen 9: 695-703
Chen, G., Bower, K.A., Ma, C., Fang, S., Thiele, C.J., and Luo, J. (2004) Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. Faseb J. 18:1162-4
Magnifico, A., Ettenberg, S., Yang, C., Mariano, J., Tiwari, S., Fang, S., Lipkowitz, S., Weissman, A.M. (2003). HECT E3s target Cbl RING finger E3s for proteasomal degradation. J Biol Chem 278:43169-77.
Doong, H., Rizzo, K., Fang, S., Kulpa, V., Weissman, A.M., Kohn, E.C. (2003). CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: accumulation of poly-ubiquitinated Hsp90 client proteins. J Biol Chem278:28490-500.
Liang, J.S., Kim, T., Fang, S., Yamaguchi, J., Weissman, A.M., Fisher, E.A., Ginsberg, H.N. (2003) Overexpression of the tumor autocrine motility factor receptor gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells. J Biol Chem 278:23984-8.
Xie, Q., Guo, H., Dallman, G., Fang, S., Weissman, A.M., and Chua, NH. (2002). SINAT5 promotes ubiquitin-related degradation of NAC1 to attenuate auxin signals. Nature 419, 167-170.
Fang, S., Ferrone, M., Yang, C., Jensen, J. P., Tiwari, S., and Weissman, A.M. (2001) The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci U S A 98, 14422-14427.
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., and Weissman, A. M. (2000). Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 275, 8945-8951.
Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M., and Ashwell, J. D. (2000). Ubiquitin Protein Ligase Activity of IAPs and Their Degradation in Proteasomes in Response to Apoptotic Stimuli. Science 288, 874-877.
Lorick, K. L., Jensen, J. P., Fang, S., Ong, A. M., Hatakeyama, S., and Weissman, A. M. (1999). RING fingers mediate ubiquitin conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A 96, 11364-11369.
Fang, S., Sharma, R. V., and Bhalla, R. C. (1999). Enhanced recovery of injury-caused downregulation of paxillin protein by eNOS gene expression in rat carotid artery. Mechanism of NO inhibition of intimal hyperplasia? Arterioscler Thromb Vasc Biol 19, 147-152.
Sharma, R. V., Tan, E., Fang, S., Gurjar, M. V., and Bhalla, R. C. (1999). NOS gene transfer inhibits expression of cell cycle regulatory molecules in vascular smooth muscle cells. Am J Physiol 276, H1450-9.
Fang, S., Sharma, R. V., and Bhalla, R. C. (1997). Endothelial nitric oxide synthase gene transfer inhibits platelet-derived growth factor-BB stimulated focal adhesion kinase and paxillin phosphorylation in vascular smooth muscle cells. Biochem Biophys Res Commun 236, 706-711.
Sharma, R. V., Fang, S., and Bhalla, R. C. (1997). Factors influencing adenovirus-mediated gene transfer to endothelial and vascular smooth muscle cells in vivo and in vitro. Recent Res Dev in Mol Biol 1, 41-49.
Cullen, J. J., Herrmann, B. M., Thomas, R. M., Fang, S., Murray, J. A., Ledlow, A., Christensen, J., and Conklin, J. L. (1997). The role of antioxidant enzymes in the control of opossum sphincter of Oddi motility. Am J Physiol 272, G1050-6.
Thomas, R. M., Fang, S., Leichus, L. S., Oberley, L. W., Christensen, J., Murray, J. A., Ledlow, A., and Conklin, J. L. (1996). Antioxidant enzymes in intramural nerves of the opossum esophagus. Am J Physiol 270, G136-42.
Christensen, J., Fang, S., and Rick, G. A. (1995). NADPH-diaphorase-positive nerve fibers in smooth muscle layers of opossum esophagus: gradients in density. J Auton Nerv Syst 52, 99-105.
Fang, S., and Christensen, J. (1995). Manganese superoxide dismutase and reduced nicotinamide adenine dinucleotide diaphorase colocalize in the rat gut. Gastroenterology 109, 1429-1436.
Fang, S., Thomas, R. M., Conklin, J. L., Oberley, L. W., and Christensen, J. (1995). Co-localization of manganese superoxide dismutase and NADH diaphorase. J Histochem Cytochem 43, 849-855.
Conklin, J. L., O’Meara, B. W., Murray, J. A., Fang, S., Clark, E. D., and Christensen, J. (1995). Effect of nitroblue tetrazolium on NO synthase and motor function of opossum esophagus. Dig Dis Sci 40, 2390-2397.
Christensen, J., and Fang, S. (1994). Colocalization of NADPH-diaphorase activity and certain neuropeptides in the esophagus of opossum (Didelphis virginiana). Cell Tissue Res 278, 557-562.
Fang, S., and Christensen, J. (1994). Distribution of NADPH diaphorase in intramural plexuses of cat and opossum esophagus. J Auton Nerv Syst 46, 123-133.
Fang, S., Ledlow, A., Murray, J. A., Christensen, J., and Conklin, J. L. (1994). Vasoactive intestinal contractor: localization in the opossum esophagus and effects on motor functions. Gastroenterology 107, 1621-1626.
Fang, S., Christensen, J., Conklin, J. L., Murray, J. A., and Clark, G. (1994). Roles of Triton X-100 in NADPH-diaphorase histochemistry. J Histochem Cytochem 42, 1519-1524.
Fang, S., Wu, R., and Christensen, J. (1993). Intramucosal nerve cells in human small intestine. J Auton Nerv Syst 44, 129-136.
Grants and Contracts
09/16/2022 – 08/31/2027 (PI. 30%)
“Pharmacological enhancement of UBA1 activity in models of VEXAS syndrome”
NIAMS/NIH 1U01AR081599-01