Feng Shao, Ph.D.
Investigator and Deputy Director for Academic Affairs, NIBS, Beijing, China
B.S. Applied Chemistry,
M.S. Molecular Biology,
Ph.D. Biological Chemistry, University of
Investigator, National Institute of Biological Sciences, Beijing, China
Associate Investigator, National Institute of Biological Sciences, Beijing, China
Assistant Investigator, National Institute of Biological Sciences, Beijing, China
Damon Runyon Postdoctoral Research Fellow, Harvard Medical School, Boston, USA
Postdoctoral Research Fellow, School of Medicine, University of California, San Diego, USA
Dr. Feng Shao’s laboratory is interested in studying molecular mechanisms of bacterial infection and host innate immunity defense. Bacterial pathogens use specialized secretion systems such as type III/IV secretion system to inject effector proteins into host cells, serving as a key and universal virulence mechanism. The effectors usually harbor a unique and potent activity that modulates the function of key signaling molecules in the host, and this plays a critical role in bacterial survival and systemic infections. Using pathogens such asShigella, Salmonella, Enteropathogenic E. coli (EPEC), Legionella and Burkholderia as the model, we are working to discover and reveal some novel and common biochemical mechanisms utilized by bacterial effectors in modulating host signal transduction pathways. Our recent work has led to several interesting discoveries. 1) The OspF family of type III effectors, conserved in Shigella,Salmonella and the plant pathogen P. syringae, harbors a novel phosphothreonine lyase activity that specifically and irreversibly “dephosphorylates” host MAPKs, leading to kinase inactivation and inhibited cytokine production. 2) The Legionellatype IV effector LegK1 mimics host IKK to phosphorylate IkBa, which results in ubiquitination and degradation of IkBa and consequent activation of host anti-apoptotic NF-kB signaling. 3) Type III effectors CHBP (Burkholderia) and Cif (EPEC) use a papain-like catalytic activity to deamidate ubiquitin and ubiquitin-like protein NEDD8. This leads to dysfunctioning of host ubiquitin-proteasome system, and therefore many important cellular processes such as cell cycle progression become abnormal. We believe that such kind of research and discovery is not only revealing in bacterial pathogenesis, but also provides an unprecedented unique angle for studying the mechanism of eukaryotic signal transduction. Meanwhile, we are also interested in how the host uses its innate immunity system to counteract bacterial infection, particularly the inflammasome pathway in macrophages. Macrophage senses many kinds of pathogen-derived molecular patterns and thereby activates the cytoplasmic inflammasome complex, and this leads to Il-1b production and inflammatory cell death of the macrophage. The NOD-like receptor in inflammasome is required for sensing bacteria-derived signals. However, little is known about how the inflammasome is assembled/activated, and the signaling cascade upstream of the inflammasome remains obscure. We are combining multiple approaches including biochemical reconstitution, cell biology and mouse genetics to identify new components in pathogen-induced inflammasome activation and to further reveal the underlying biochemical mechanism.
1. Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L & Shao F. (2014) Inflammatory caspases are innate immune receptors for intracellular LPS,Nature (Article), 514, 187-192 (Published online 06 August 2014).
2. Lu Q, Yao Q, Xu Y, Li L, Li S, Liu Y, Gao W, Niu M, Sharon M, Ben-Nissan G, Zamyatina A, Liu X, Chen S & Shao F. (2014) Hyper-heptosylation of Bacterial Autotransporters by an Iron-containing Dodecameric Glycosyltransferase Family in Pathogenesis, Cell Host & Microbe, 16, 351–363.
3. Xu H, Yang J, Gao W, Li L, Li P, Zhang L, Gong YN, Peng X, Xi JJ, Chen S, Wang F, Shao F. (2014) Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature, 513, 237–241 (Published online 11 June 2014).
4. Li S, Zhang L, Yao Q, Li L, Dong N, Rong J, Gao W, Ding X, Sun L, Chen X, Chen S & Shao F. (2013) Pathogen blocks host death receptor signaling by arginine GlcNAcylation of death domains. Nature, 501, 242-246.
5. Yang J, Zhao Y, Shi J & Shao F. (2013) Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation. Proc. Natl. Acad. Sci., 110, 14408-13.
6. Dong N, Zhu Y, Lu Q, Hu L, Zheng Y, Shao F. (2012) Structurally distinct bacterial TBC-like GAPs link Arf GTPase to Rab1 inactivation to counteract host defenses. Cell, 150, 1029-41.
7. Zhang L, Ding X, Cui J, Xu H, Chen J, Gong YN, Hu L, Zhou Y, Ge J, Lu Q, Liu L, Chen S, Shao F. (2012) Cysteine methylation disrupts ubiquitin-chain sensing in NF-kB activation. Nature, 481, 204-8.
8. Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, Liu L, Shao F. (2011) The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature, 477, 596–600.
9. Cui J, Yao Q, Li S, Ding X, Lu Q, Mao H, Liu L, Zheng N, Chen S, Shao F. (2010) Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family. Science, 329, 1215-8.
10. Li H, Xu H, Zhou Y, Zhang J, Long C, Li S, Chen S, Zhou JM, Shao F. (2007) The phosphothreonine lyase activity of a bacterial type III effector family.Science, 315, 1000-3.
11. Yao Q, Zhang L, Wan X, Chen J, Hu L, Ding X, Li L, Karar J, Peng H, Chen S, Huang N, Rauscher FJ, Shao F. (2014) Structure and specificity of the bacterial cysteine methyltransferase effector NleE suggests a novel substrate in human DNA repair pathway. PLoS Pathogens, in press.
12. Yao Q, Lu Q, Wan X, Song F, Xu Y, Zamyatina A, Huang N, Zhu P & Shao F. (2014) A structural mechanism for bacterial autotransporter glycosylation by a dodecameric heptosyltransferase family, eLife, Oct 13. doi: 10.7554/eLife.03714. [Epub ahead of print].
13. Pan M, Li S, Li X, Shao F, Liu L and Hu HG (2014) Synthesis and Specific Antibody Generation of Glycopeptides with Arginine N-GlcNAcylation. Angew Chem Int Ed Engl. in press (co-corresponding author).
14. Lu Q, Xu Y, Yao Q, Niu M and Shao F. (2014) A polar-localized iron-binding protein determines the polar targeting of Burkholderia BimA autotransporter and actin tail formation, Cellular Microbiology, 2014 Oct 8. doi: 10.1111/cmi.12376. [Epub ahead of print].
15. Ding J, Luo AF, Hu L, Wang DC, Shao F. (2014) Structural basis of the ultrasensitive calcium indicator GCaMP6. SCIENCE CHINA Life Sciences, 57, 269–274.
16. Li T, Lu Q, Wang G, Xu H, Huang H, Cai T, Kan B, Ge J & Shao F. (2013) SET-domain bacterial effectors target heterochromatin protein 1 to activate host rDNA transcription. EMBO Reports, 14, 733-40.
17. Yu Q, Hu L, Yao Q, Zhu Y, Dong N, Wang DC, Shao F. (2013) Structural analyses of a Legionella RabGAP effector reveal a new GAP fold that catalytically mimics eukaryotic RasGAP. Cell Research, 23, 775-87.
18. Zhou Y, Dong N, Hu L, Shao F. (2013) The Shigella Type Three Secretion System Effector OspG Directly and Specifically Binds to Host Ubiquitin for Activation. PLoS One, 8: e57558.
19. Yao Q, Cui J, Wang J, Li T, Wan X, Luo T, Gong YN, Xu Y, Huang N, Shao F. (2012) Structural mechanism of ubiquitin and NEDD8 deamidation catalyzed by bacterial effectors that induce macrophage-specific apoptosis. Proc. Natl. Acad. Sci., 109, 20395-400.
20. Ku B, Lee KH, Park WS, Yang CS, Ge J, Lee SG, Cha SS, Shao F, Heo WD, Jung JU, Oh BH. (2012) VipD of Legionella pneumophila targets activated Rab5 and Rab22 to interfere with endosomal trafficking in macrophages. PLoS Pathogen, 8, e1003082.
21. Ge J, Gong YN, Xu Y, Shao F. (2012) Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking. Proc. Natl. Acad. Sci., 109, 6193-8.
22. Zhao Y, Shao F. (2012) NLRC5: a NOD-like receptor protein with many faces in immune regulation. Cell Research, 22, 1099-101. (invited review)
23. Gong YN, Shao F. (2012) Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation. Protein & Cell, 3, 98-105. (invited review)
24. He S, Liang Y, Shao F, Wang X. (2011) Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3–mediated pathway. Proc. Natl. Acad. Sci., 108, 20054-9.
25. Li C, Tu S, Wen S, Li S, Chang J, Shao F, and Lei X. (2011) Total Synthesis of the G2/M DNA Damage Checkpoint Inhibitor Psilostachyin C. The Journal of Organic Chemistry, 76, 3566-70.
26. Ge J, Shao F. (2011) Manipulation of host vesicular trafficking and innate immune defense by Legionella Dot/Icm effectors. Cell. Microbiol., 13, 1870-80. (invited review)
27. Cui J, Shao F. (2011) Biochemistry and cell signaling taught by bacterial effectors. Trends in Biochemical Sciences, 36, 532-40. (invited review)
28. Gong YN, Wang X, Wang J, Yang Z, Li S, Yang J, Liu L, Lei X, Shao F. (2010) Chemical probing reveals insights into the signaling mechanism of inflammasome activation. Cell Research, 20, 1289-305.
29. Dong N, Liu L, Shao F. (2010) A bacterial effector targets host DH-PH domain RhoGEFs and antagonizes macrophage phagocytosis. The EMBO J., 29, 1363-76.
30. Zhu Y, Hu L, Zhou Y, Yao Q, Liu L, Shao F. (2010) Structural mechanism of host Rab1 activation by the bifunctional Legionella type IV effector SidM/DrrA.Proc. Natl. Acad. Sci., 107, 4699-704.
31. Ge J, Xu H, Li T, Zhou Y, Zhang Z, Li S, Liu L, Shao F. (2009) A Legionella type IV effector activates the NF-κB pathway by phosphorylating the IκB family of inhibitors. Proc. Natl. Acad. Sci., 106, 13725-30.
32. Chen Y, Yang Z, Meng M, Zhao Y, Dong N, Yan H, Liu L, Ding M, Peng, HB,Shao F. (2009) Cullin mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement. Mol. Cell, 35, 841-55.
33. Dowen RH, Engel JL, Shao F, Ecker JR, Dixon JE. (2009) A family of bacterial cysteine protease type III effectors utilizes acylation-dependent and -independent strategies to localize to plasma membranes. J. Biol. Chem., 284, 15867-79.
34. Yao Q, Cui J, Zhu Y, Wang G, Hu L, Long C, Cao, R, Liu X, Huang N, Chen S, Liu L, Shao F. (2009) A bacterial type III effector family uses the papain-like hydrolytic activity to arrest the host cell cycle. Proc. Natl. Acad. Sci., 106, 3716-21.
35. Zhu Y., Li H., Hu L., Wang, J., Zhou Y., Pang Z., Liu L., Shao F. (2008) Structure of a Shigella effector reveals a new class of ubiquitin ligases. Nature Structural & Molecular Biology, 15, 1302-8.
36. Shao F. (2008) Biochemical functions of Yersinia type III effectors. Current Opinion in Microbiology, 11, 21-9. (invited review)
37. Zhu Y, Li H, Long C, Hu L, Xu H, Liu L, Chen S, Wang DC, Shao F. (2007) Structural insights into the enzymatic mechanism of the pathogenic MAPK phosphothreonine lyase. Mol. Cell, 28, 899-913.
38. Zhang J, Shao F, Li Y, Cui H, Chen L, Li H, Zou Y, Long C , Lan L, Chai J, Chen S, Tang X, Zhou JM. (2007) A Pseudomonas syringae effector inactivates MAPKs to suppress PAMP-induced immunity. Cell Host & Microbe, 1, 175-85.
39. Alto NM, Shao F, Lazar CS, Brost RL, Chua G, Mattoo, SM, McMahon SA, Ghosh P, Hughes TR, Boone C, Dixon JE. (2006) Identification of a bacterial type III effector family with G-protein mimicry functions. Cell, 124, 133-45.
40. Armstrong MB, Bian X, Liu Y, Subramanian C, Ratanaproeska AB, Shao F, Yu V, Kwok R, Opipari AW, Jr., Castle VP. (2006) Signaling from p53 to NF-kappaB determines chemotherapy responsiveness of neuroblastoma. Neoplasia, 8, 964-74.
41. Zhu M, Shao F, Innes RW, Dixon JE, Xu Z. (2004) The crystal structure ofPseudomonas avirulence protein AvrPphB: a papain-like fold with a distinct substrate-binding site. Proc. Natl. Acad. Sci., 101, 302-7.
42. Shao F, Golstein, C, Ade J, Stoutemyer M., Dixon JE, Innes RW. (2003) Cleavage of Arabidopsis PBS1 by a bacterial type III effector. Science, 301, 1230-3.
43. Shao F, Vacratsis PO, Bao Z, Bowers KE, Fierke CA, Dixon JE. (2003) Biochemical characterization of the Yersinia YopT protease: cleavage site and recognition elements in Rho GTPases. Proc. Natl. Acad. Sci., 100, 904-9.
44. Shao F, Merritt PM, Bao Z, Innes RW, Dixon JE. (2002) A Yersinia effector and a Pseudomonas avirulence protein define a family of cysteine proteases functioning in bacterial pathogenesis. Cell, 109, 575-88.
45. Juris SJ, Shao F, Dixon JE. (2002) Yersinia effectors target mammalian signaling pathways. Cell. Microbiol., 4: 201-11 (Co-first author, invited review).
46. Bian X, McAllister-Lucas LM, Shao F, Schumacher KR, Feng Z, Porter AG, Castle VP, Opipari AW, Jr. (2001) NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells. J. Biol. Chem., 276, 48921-9.
47. Shao F, Bader MW, Jakob U, Bardwell JC. (2000) DsbG, a protein disulfide isomerase with chaperone activity. J. Biol. Chem., 275, 13349-52.
48. Wang CG, He XL, Shao F, Liu W, Ling MH, Wang DC, Chi CW. (2001) Molecular characterization of an anti-epilepsy peptide from the scorpion Buthus martensi Karsch. Eur. J. Biochem., 268, 2480-5.
49. Shao F, Hu Z, Xiong YM, Huang QZ, Wang CG, Zhu RH, Wang DC. (1999) A new antifungal peptide from the seeds of Phytolacca americana: characterization, amino acid sequence and cDNA cloning. Biochim. Biophys. Acta, 1430, 262-8.
50. Shao F, Xiong YM, Zhu RH, Ling M, Chi CW, Wang DC. (1999) Expression and purification of the BmK M1 neurotoxin from the scorpion Buthus martensii Karsch. Protein Expr. Purif., 17, 358-65.