实验室的研究兴趣集中在病原细菌和宿主相互作用机理的探索方面，在致病菌毒力机制以及抗细菌天然免疫方向均已取得一系列重要原创发现：发现细菌内毒素(LPS)、鞭毛以及三型分泌系统的胞内天然免疫受体，并揭示了这些受体下游炎性caspase通过剪切活化Gasdermin D (GSDMD)蛋白诱导细胞焦亡的确切分子机制，其中有关Gasdermin 家族蛋白的鉴定和机制的阐述将细胞焦亡概念重新定义为——由Gasdermin 家族介导的细胞程序性坏死；发现被化疗药物激活的caspase-3可直接切割并激活Gasdermin E (GSDME) 蛋白，进而诱导细胞焦亡产生毒副作用，颠覆了caspase-3诱导细胞凋亡的教科书观点，重新将天然免疫应答中的细胞焦亡定义为由Gasdermin家族蛋白介导的细胞程序化死亡，揭示了癌症化疗药物毒副作用的一个重要原因。在最新的工作中，从应用转化角度出发，利用三氟化硼脱硅反应的“双靶向激活”策略效率高、生物正交性好的优势，实现在肿瘤原位进行可控的细胞焦亡激活，首次揭示了细胞焦亡可高效诱导机体产生抗肿瘤免疫活性，即只需少部分的肿瘤细胞发生焦亡，就足以有效调节肿瘤免疫微环境，激活很强的T细胞介导的抗肿瘤免疫反应，进而有效清除肿瘤；发现细胞毒性淋巴细胞可以通过分泌的颗粒酶切割活化GSDMB蛋白，进而诱导肿瘤细胞发生焦亡而实现对肿瘤的清除，颠覆了教科书中细胞毒性淋巴细胞是通过细胞凋亡清除靶细胞的传统认知。

RepresentativePublications:

1.     Zhou Z, He H, Wang K, Shi X,Wang Y, Su Y, Wang Y, Li D, Liu W, Zhang Y, Shen L, Han W, Shen L, Ding J, Shao F. (2020) Granzyme A fromcytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells, Science,368, eaaz7548.

2.     Wang Q, Wang Y, Ding J, Wang C,Zhou X, Gao W, Huang H, Shao F*, LiuZ*. (2020) A bioorthogonalsystem reveals antitumour immune function of pyroptosis, Nature,579, 421-426.

3.     Wang K, Sun Q, Zhong X, Zeng M,Zeng H, Shi X, Li Z, Wang Y, Zhao Q, ShaoF*, Ding J*. (2020) Structuralmechanism for GSDMD targeting by autoprocessed caspases in pyroptosis,Cell,180, 941-955.

4.    Xu Y, Zhou P, Cheng S, Lu Q, Nowak K, Hopp A, Li L, Shi X, Zhou Z,Gao W, Li D, He H, Liu X, Ding J, Hottiger M, Shao F. (2019) ABacterial effector reveals the V-ATPase-ATG16L1 axis that initiatesxenophagy, Cell, 178, 1-15.

5.    Zhou P, She Y, Dong N, Li P, He H, Borio A, Wu Q, Lu S, Ding X,Cao Y, Xu Y, Gao W, Dong M, Ding J, Wang DC, Zamyatina A, Shao F. (2018)Alpha-kinase 1 is a cytosolic innate immune receptor for bacterialADP-heptose, Nature, 561, 122-126 (Published online Aug 15).

6.    Li P, Jiang W, Yu Q, Liu W, Zhou P, Li J, Xu J, Xu B, Wang F& Shao F. (2017) Ubiquitination and degradation of GBPs bya Shigella effector to suppress host defense, Nature,551, 378-383 (Published online Oct 11).

7.    Wang Y, Gao W, Shi X, Ding J, Liu W, He H, Wang K & ShaoF. (2017) Chemotherapy drugs induce pyroptosis through caspase-3 cleavageof a Gasdermin, Nature, 547 (7661), 99-103 (Published onlineMay 01).

8.    Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang DC& Shao F. (2016) Pore-forming activity and structuralautoinhibition of the Gasdermin family, Nature (Article),535 (7610), 111-116 (Published online 08 June 2016).

9.    Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T,Wang F & Shao F. (2015) Cleavage of GSDMD by inflammatorycaspases determines pyroptotic cell death, Nature (Article),526, 660–665.

10.  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) Aniron-containing dodecameric heptosyltransferase family modifies bacterialautotransporters in pathogenesis, Cell Host & Microbe,16, 351–363.

11.  Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L & ShaoF. (2014) Inflammatory caspases are innate immune receptors forintracellular LPS, Nature (Article), 514, 187-192 (Publishedonline 06 August 2014).

12.  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 bacterialmodifications of Rho GTPases by the Pyrin inflammasome. Nature,513, 237–241 (Published online 11 June 2014).

13.  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 deathreceptor signaling by arginine GlcNAcylation of death domains. Nature,501, 242-246.

14.  Yang J, Zhao Y, Shi J & Shao F. (2013) Human NAIPand mouse NAIP1 recognize bacterial type III secretion needle protein forinflammasome activation. Proc. Natl. Acad. Sci., 110,14408-13.

15.  Dong N, Zhu Y, Lu Q, Hu L, Zheng Y, Shao F. (2012)Structurally distinct bacterial TBC-like GAPs link Arf GTPase to Rab1inactivation to counteract host defenses. Cell, 150,1029-41.

16.  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 disruptsubiquitin-chain sensing in NF-kB activation. Nature, 481,204-8.

17.  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 typeIII secretion apparatus. Nature, 477, 596–600.

18.  Cui J, Yao Q, Li S, Ding X, Lu Q, Mao H, Liu L, Zheng N, ChenS, Shao F. (2010) Glutamine deamidation and dysfunction ofubiquitin/NEDD8 induced by a bacterial effector family. Science,329, 1215-8.

19.  Li H, Xu H, Zhou Y, Zhang J, Long C, Li S, Chen S, Zhou JM, ShaoF. (2007) The phosphothreonine lyase activity of a bacterial type IIIeffector family. Science, 315, 1000-3.

OtherPublications:

Research articles:

1.    Ding J, Pan X, Du L, Yao Q, Xue J, Yao H, Wang D, Li S, Shao F.(2019) Structural and functional insights into host death domains inactivationby the bacterial arginine GlcNAcyltransferase effector, Molecular Cell, 74,1-14.

2.    Rathinam V, Zhao Y, Shao F. (2019) Innate immunity tointracellular LPS, Nature Immunology, 20, 527-533.

3.    Xu H, Shi J, Gao H, Liu Y, Yang Z, Shao F, Dong N.(2019) The N-end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasomeactivation by anthrax lethal toxin, EMBO, 38(13):e101996.

4.    Liu W, Zhou Y, Peng T, Zhou P, Ding X, Li Z, Chen S, Hang HC,and Shao F. (2018) Ne-fatty acylation of multiplemembrane-associated proteins by Shigella IcsB effector tomodulate host function, Nature Microbiology, 3, 996-1009.

5.    Adanitsch F, Shi J, Shao F, Beyaert R, Heine H, and ZamyatinaA. (2018) Synthetic glycan-based TLR4 agonists targeting Caspase-4/11 for thedevelopment of adjuvants and immunotherapeutics, Chem. Sci., 9,3957-3963.

6.    Yang J, Zhao Y, Li P, Yang Y, Zhang E, Zhong M, Li Y, Zhou D, CaoY, Lu M, Shao F#, Yan H#. (2018) Sequence determinants of specificpattern-recognition of bacterial ligands by the NAIP-NLRC4 inflammasome, CellDiscovery,4: 22. doi: 10.1038/s41421-018-0018-1 (# correspondingauthors).

7.    Lin R, Feng Q, Li P, Zhou P, Wang R, Liu Z, Wang Z, Qi X, Tang N, ShaoF, Luo M. (2018). A hybridization-chain-reaction-based method foramplifying immunosignals, Nature Methods,15, 275-278.

8.    Xu B, Jiang M, Chu Y, Wang W, Chen D, Li X, Zhang Z, Zhang D, FanD, Nie Y, Shao F, Wu K, Liang J. (2018) Gasdermin D plays a keyrole as a pyroptosis executor of non-alcoholic steatohepatitis in humans andmice, J Hepatol., 68, 773-782.

9.    Zhou Y, Huang C, Yin L, Wan M, Wang X, Li L, Liu Y, Wang Z, Fu P,Zhang N, Chen S, Liu X, Shao F, Zhu Y. (2017). Nε-Fattyacylation of Rho GTPases by a MARTX toxin effector, Science.358, 528-531.

10.  Sheng X, You Q, Zhu H, Chang Z, Li Q, Wang H, Wang C, Wang H, HuiL, Du C, Xie X, Zeng R, Lin A, Shi D, Ruan K, Yan J, Gao GF, Shao F,Hu R. (2017) Bacterial effector NleL promotes enterohemorrhagic E. coli-inducedattaching and effacing lesions by ubiquitylating and inactivating JNK, PLoSPathogen,13(7): e1006534.

11.  Litvak Y, Sharon S, Hyams M, Zhang L, Kobi S, Katsowich N, DishonS, Nussbaum G, Dong N, Shao F, and Rosenshine I. (2017) Epithelialcells detect functional type III secretion system of enteropathogenic Escherichiacoli through a novel NF-κB signaling pathway. PLoS Pathogen,13(7): e1006472.

12.  Dong N, Niu M, Hu L, Yao Q, Zhou R, and Shao F. (2016)Modulation of membrane phosphoinositide dynamics by the phosphatidylinositide4-kinase activity of the Legionella LepB effector, NatureMicrobiology, 2:16236.

13.  Thurston TL, Matthews SA, Jennings E, Alix E, Shao F,Shenoy AR, Birrell MA, Holden DW. (2016) Growth inhibition ofcytosolic Salmonella by caspase-1 and caspase-11 precedes hostcell death, Nature Communications, 7:13292.

14.  Gao W, Yang J, Liu W, Wang Y, Shao F. (2016)Site-specific phosphorylation and microtubule dynamics control Pyrininflammasome activation, Proc. Natl. Acad. Sci., 113,E4857-66.

15.  Zhang Q, Zhou A, Li S, Ni J, Tao J, Lu J, Wan B, Li S, Zhang J,Zhao S, Zhao GP, Shao F, Yao YF (2016) Reversible lysineacetylation is involved in DNA replication initiation by regulating activitiesof initiator DnaA in Escherichia coli, Sci Rep.,6: 30837.

16.  Aubert DF, Xu H, Yang J, Gao W, Li L, Chen S, Valvano MA, ShaoF. (2016) A Burkholderia type VI effector deamidates RhoGTPases to activate the Pyrin inflammasome, Cell Host & Microbe,19, 664-674.

17.  Zhao Y, Shi J, Shi X, Wang Y, Wang F & Shao F.(2016) Genetic functions of the NAIP family of inflammasome receptors forbacterial ligands in mice, Journal of Experimental Medicine,213(5), 647-56.

18.  Zanoni I, Tan Y, Di Gioia M, Broggi A, Ruan J, Shi J, DonadoCA, Shao F, Wu H, Springstead JR, Kagan JC. (2016) An endogenouscaspase-11 ligand elicits interleukin-1 release from living dendriticcells, Science, 352(6290), 1232-6.

19.  Hu Z, Zhou Q, Zhang C, Fan S, Cheng W, Zhao Y, Shao F,Wang HW, Sui SF, Chai J. (2015) Structural and biochemical basis for inducedself-propagation of NLRC4, Science, 350, 399-404.

20.  Lu Q, Xu Y, Yao Q, Niu M and Shao F. (2015) Apolar-localized iron-binding protein determines the polar targeting of Burkholderia BimAautotransporter and actin tail formation, Cellular Microbiology,17, 408–424.

21.  Yao Q, Zhang L, Wan X, Chen J, Hu L, Ding X, Li L, Karar J, PengH, Chen S, Huang N, Rauscher FJ, Shao F. (2014) Structure andSpecificity of the Bacterial Cysteine Methyltransferase Effector NleE Suggestsa Novel Substrate in Human DNA Repair Pathway. PLoS Pathogens,10: e1004522.

22.  Yao Q, Lu Q, Wan X, Song F, Xu Y, Zamyatina A, Huang N, Zhu P& Shao F. (2014) A structural mechanism for bacterialautotransporter glycosylation by a dodecameric heptosyltransferasefamily, eLife, 3: e03714.

23.  Pan M, Li S, Li X, Shao F, Liu L and Hu HG (2014)Synthesis and Specific Antibody Generation of Glycopeptides with ArginineN-GlcNAcylation. Angew Chem Int Ed Engl., 53,14517-14521 (co-corresponding author).

24.  Ding J, Luo AF, Hu L, Wang DC, Shao F. (2014)Structural basis of the ultrasensitive calcium indicator GCaMP6. SCIENCECHINA Life Sciences, 57, 269–274.

25.  Li T, Lu Q, Wang G, Xu H, Huang H, Cai T, Kan B, Ge J & ShaoF. (2013) SET-domain bacterial effectors target heterochromatin protein 1to activate host rDNA transcription. EMBO Reports, 14,733-40.

26.  Yu Q, Hu L, Yao Q, Zhu Y, Dong N, Wang DC, Shao F.(2013) Structural analyses of a Legionella RabGAP effectorreveal a new GAP fold that catalytically mimics eukaryotic RasGAP. CellResearch, 23, 775-87.

27.  Zhou Y, Dong N, Hu L, Shao F. (2013) The Shigella TypeThree Secretion System Effector OspG Directly and Specifically Binds to HostUbiquitin for Activation. PLoS One, 8: e57558.

28.  Yao Q, Cui J, Wang J, Li T, Wan X, Luo T, Gong YN, Xu Y, HuangN, Shao F. (2012) Structural mechanism of ubiquitin and NEDD8deamidation catalyzed by bacterial effectors that induce macrophage-specificapoptosis. Proc. Natl. Acad. Sci., 109, 20395-400.

29.  Ku B, Lee KH, Park WS, Yang CS, Ge J, Lee SG, Cha SS, ShaoF, Heo WD, Jung JU, Oh BH. (2012) VipD of Legionella pneumophila targetsactivated Rab5 and Rab22 to interfere with endosomal trafficking inmacrophages. PLoS Pathogen, 8: e1003082.

30.  Ge J, Gong YN, Xu Y, Shao F. (2012) Preventingbacterial DNA release and absent in melanoma 2 inflammasome activation bya Legionella effector functioning in membranetrafficking. Proc. Natl. Acad. Sci., 109, 6193-8.

31.  He S, Liang Y, Shao F, Wang X. (2011) Toll-likereceptors activate programmed necrosis in macrophages through areceptor-interacting kinase-3–mediated pathway. Proc. Natl. Acad.Sci., 108, 20054-9.

32.  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 PsilostachyinC. The Journal of Organic Chemistry, 76, 3566-70.

33.  Gong YN, Wang X, Wang J, Yang Z, Li S, Yang J, Liu L, Lei X, ShaoF. (2010) Chemical probing reveals insights into the signaling mechanism ofinflammasome activation. Cell Research, 20, 1289-305.

34.  Dong N, Liu L, Shao F. (2010) A bacterial effectortargets host DH-PH domain RhoGEFs and antagonizes macrophagephagocytosis. The EMBO J., 29, 1363-76.

35.  Zhu Y, Hu L, Zhou Y, Yao Q, Liu L, Shao F. (2010)Structural mechanism of host Rab1 activation by the bifunctional Legionella typeIV effector SidM/DrrA. Proc. Natl. Acad. Sci., 107,4699-704.

36.  Ge J, Xu H, Li T, Zhou Y, Zhang Z, Li S, Liu L, Shao F. (2009) A Legionella typeIV effector activates the NF-κB pathway by phosphorylating the IκB family ofinhibitors. Proc. Natl. Acad. Sci., 106, 13725-30.

37.  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 RhoAthrough evolutionarily conserved BTB adaptors to control actin cytoskeletonstructure and cell movement. Mol. Cell, 35, 841-55.

38.  Dowen RH, Engel JL, Shao F, Ecker JR, Dixon JE. (2009)A family of bacterial cysteine protease type III effectors utilizes acylation-dependentand -independent strategies to localize to plasma membranes. J.Biol. Chem., 284, 15867-79.

39.  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 familyuses the papain-like hydrolytic activity to arrest the host cell cycle. Proc.Natl. Acad. Sci., 106, 3716-21.

40.  Zhu Y., Li H., Hu L., Wang, J., Zhou Y., Pang Z., Liu L., ShaoF. (2008) Structure of a Shigella effector reveals anew class of ubiquitin ligases. Nature Structural & MolecularBiology, 15, 1302-8.

41.  Zhu Y, Li H, Long C, Hu L, Xu H, Liu L, Chen S, Wang DC, ShaoF. (2007) Structural insights into the enzymatic mechanism of thepathogenic MAPK phosphothreonine lyase. Mol. Cell, 28,899-913.

42.  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 Pseudomonassyringae effector inactivates MAPKs to suppress PAMP-inducedimmunity. Cell Host & Microbe, 1, 175-85.

43.  Alto NM, Shao F, Lazar CS, Brost RL, Chua G, Mattoo,SM, McMahon SA, Ghosh P, Hughes TR, Boone C, Dixon JE. (2006) Identification ofa bacterial type III effector family with G-protein mimicry functions. Cell, 124,133-45.

44.  Armstrong MB, Bian X, Liu Y, Subramanian C, Ratanaproeska AB, ShaoF, Yu V, Kwok R, Opipari AW, Jr., Castle VP. (2006) Signaling from p53 toNF-kappaB determines chemotherapy responsiveness of neuroblastoma. Neoplasia,8, 964-74.

45.  Zhu M, Shao F, Innes RW, Dixon JE, Xu Z. (2004) Thecrystal structure of Pseudomonas avirulence protein AvrPphB: apapain-like fold with a distinct substrate-binding site. Proc. Natl.Acad. Sci., 101, 302-7.

46.  Shao F, Golstein, C, Ade J,Stoutemyer M., Dixon JE, Innes RW. (2003) Cleavage of Arabidopsis PBS1by a bacterial type III effector. Science, 301, 1230-3.

47.  Shao F, Vacratsis PO, Bao Z, BowersKE, Fierke CA, Dixon JE. (2003) Biochemical characterization of the YersiniaYopTprotease: cleavage site and recognition elements in Rho GTPases. Proc.Natl. Acad. Sci., 100, 904-9.

48.  Shao F, Merritt PM, Bao Z, Innes RW,Dixon JE. (2002) A Yersinia effector and a Pseudomonas avirulenceprotein define a family of cysteine proteases functioning in bacterialpathogenesis. Cell, 109, 575-88.

49.  Bian X, McAllister-Lucas LM, Shao F, Schumacher KR,Feng Z, Porter AG, Castle VP, Opipari AW, Jr. (2001) NF-kappa B activationmediates doxorubicin-induced cell death in N-type neuroblastoma cells. J.Biol. Chem., 276, 48921-9.

50.  Shao F, Bader MW, Jakob U, BardwellJC. (2000) DsbG, a protein disulfide isomerase with chaperone activity. J.Biol. Chem., 275, 13349-52.

51.  Wang CG, He XL, Shao F, Liu W, Ling MH, Wang DC, ChiCW. (2001) Molecular characterization of an anti-epilepsy peptide from thescorpion Buthus martensi Karsch. Eur. J. Biochem., 268,2480-5.

52.  Shao F, Hu Z, Xiong YM, Huang QZ,Wang CG, Zhu RH, Wang DC. (1999) A new antifungal peptide from the seedsof Phytolacca americana: characterization, amino acid sequence andcDNA cloning. Biochim. Biophys. Acta, 1430, 262-8.

53.  Shao F, Xiong YM, Zhu RH, Ling M, ChiCW, Wang DC. (1999) Expression and purification of the BmK M1 neurotoxin fromthe scorpion Buthus martensii Karsch. Protein Expr.Purif., 17, 358-65.

a)    Invited review articles:

54.  Ding J, Shao F. (2018) Growing a gasdermin pore inmembranes of pyroptotic cells. The EMBO J., 37(15). pii:e100067.

55.  Basler M, Shao F. (2018) Bacterial infection andsymbiosis. Mol Biol Cell. 29 (6), 683-684.

56.  Galluzzi L, ¼, Shao F, ¼, Kroemer, G. (2018)Molecular mechanisms of cell death: recommendations of the NomenclatureCommittee on Cell Death 2018. Cell Death & Differentiation,25 (3), 486-541.

57.  Schroder K, Kanneganti TD, Shao F, Broz P. (2018)Mechanisms of Inflammasome Activation. J Mol Biol., 430 (2),131-132.

58.  Ding J, Shao F. (2017) SnapShot: The NoncanonicalInflammasome, Cell, 168:544-544.e1.

59.  Shi J, Gao W, Shao F. (2017) Pyroptosis:Gasdermin-mediated programmed necrotic cell death, Trends inBiochemical Sciences, 42 (4), 245–254.

60.  Zhao Y, Shao F. (2016) Diverse mechanisms forinflammasome sensing of cytosolic bacteria and bacterial virulence, CurrentOpinion in Microbiology, 29, 37-42.

61.  Lu Q, Li Shan, Shao F. (2015) Sweet talk: proteinglycosylation in bacterial interaction with the host. Trends inMicrobiology, 23, 630-41 (Cover article).

62.  Zhao Y, Shao F. (2015) The NAIP-NLRC4 inflammasome ininnate immune detection of bacterial flagellin and type III secretionapparatus. Immunological Reviews, 265, 85-102.

63.  Yang J, Zhao Y, Shao F. (2015) Non-canonicalactivation of inflammatory caspases by cytosolic LPS in innate immunity. CurrentOpinion in Immunology, 32, 78-83.

64.  Yang J, Xu H, Shao F. (2014) The immunologicalfunction of familial Mediterranean fever disease protein Pyrin. SCIENCECHINA Life Sciences, 57, 1156-1161.

65.  Zhao Y, Shao F. (2012) NLRC5: a NOD-like receptorprotein with many faces in immune regulation. Cell Research,22, 1099-101.

66.  Gong YN, Shao F. (2012) Sensing bacterial infectionsby NAIP receptors in NLRC4 inflammasome activation. Protein &Cell, 3, 98-105.

67.  Ge J, Shao F. (2011) Manipulation of host vesiculartrafficking and innate immune defense by Legionella Dot/Icm effectors. Cell.Microbiol., 13, 1870-80.

68.  Cui J, Shao F. (2011) Biochemistryand cell signaling taught by bacterial effectors. Trends inBiochemical Sciences, 36, 532-40.

69.  Shao F. (2008) Biochemical functionsof Yersinia type III effectors. Current Opinion inMicrobiology, 11, 21-9.

70.  Juris SJ, Shao F, Dixon JE. (2002) Yersinia effectorstarget mammalian signaling pathways. Cell. Microbiol., 4,201-11 (Co-first author).