Tsan Sam Xiao graduated from Zhejiang University in Hangzhou, China with a Bachelor's degree in Biological Sciences and Technology. He subsequently received a Master's degree in Developmental Biology from the Chinese Academy of Sciences in 1995. He then came to the US and studied the structures of death domains from the Drosophila proteins Pelle and Tube implicated in fly development and innate immunity, for which he received his Ph.D. in molecular biophysics at the University of Texas Southwestern Medical Center at Dallas in 2000. He continued his postdoctoral training with Dr. Timothy Springer at the Harvard Medical School focusing on cell adhesion receptors such as integrins and ICAMs, both of which play important roles in immune surveillance, thrombosis, and tumor metastasis. He established his own laboratory at NIH in 2006 investigating the structures of innate immune receptors, inflammasomes, and adapter molecules implicated in antimicrobial host defense and inflammatory disorders. Dr. Xiao joined the faculty at the Case Western Reserve University's Department of Pathology in 2014. The current focus of the Xiao lab is the molecular mechanism of pyroptosis, a highly inflammatory form of cell death; and modulation of inflammatory caspases using chemical biology approaches to target inflammatory disorders.
The Xiao lab uses structural and chemical biology approaches to study the inflammasome signaling pathways, with the goal of targeting diverse diseases such as sepsis, multiple sclerosis, and AIDS using small molecule compounds. Two areas of active research are as follows:
Molecular mechanism of pyroptosis mediated by the gasdermin family of pore-forming proteins
Pyroptosis is an inflammatory form of programmed cell death that plays important roles in immune protection against infections and in inflammatory disorders. Gasdermin D (GSDMD) is an executor of pyroptosis upon cleavage by inflammatory caspases-1/4/5/11 following canonical and noncanonical inflammasome activation. GSDMD N-terminal domain assembles membrane pores to induce cytolysis, whereas its C-terminal domain inhibits cell death through intramolecular association with the N domain. The GSDMD pores also contribute to the release of mature cytokines such as IL-1β and IL-18, which in turn recruit more immune cells implicated in inflammation. Our ongoing study of GSDMD revealed its distinct mode of intramolecular domain interaction and autoinhibition, which may be relevant to its unique role in pyroptosis downstream of inflammasome activation. It remains to be determined how most of the gasdermin family members are maintained in their autoinhibited states and how they are activated through protease cleavage or other post-translational modifications, and ultimately how they function under physiological and pathological conditions. Understanding the molecular mechanisms of gasdermin transformation from soluble proteins to transmembrane pores will provide valuable insights into the roles of pyroptosis in immune protection against infections and in inflammatory disorders. These will pave the way for therapeutic targeting of various inflammatory disorders such as sepsis, multiple sclerosis and inflammatory bowel disease.
Regulation of inflammatory caspases using chemical biology approaches for drug development
Caspase is a family of cysteine proteases that are expressed as zymogens activated through autocleavage. Mature caspases predominantly cleave at P1-site aspartate residues within their substrates and play crucial roles in cell death, tissue remodeling, and differentiation. Caspases can be divided into inflammatory caspases (such as caspases-1, -4, -5, and -12 in humans and caspases-1, -11, and -12 in mice) and apoptotic caspases (such as caspases-2, -3, -6, -7, -8, -9, and -10). Even though inflammatory caspases-1, -4, -5, and -11 all cleave GSDMD, only caspase-1 cleaves pro-IL-1β and a number of other substrates. The molecular mechanisms of such substrate specificity are poorly understood, but may implicate regions outside the cleavage site (the “exosites”) that contribute to specific enzyme-substrate recognition. Our recent study demonstrated that a GSDMD-derived inhibitor, N-acetyl-Phe-Leu-Thr-Asp-chloromethylketone (Ac-FLTD-CMK), inhibits GSDMD cleavage by caspases-1, -4, -5, and -11 in vitro, suppresses pyroptosis downstream of both canonical and noncanonical inflammasomes, as well as reduces IL-1β release following inflammasome activation. By contrast, the inhibitor does not target caspase-3 or apoptotic cell death, suggesting that Ac-FLTD- CMK is a specific inhibitor for inflammatory caspases. This is significant because few inhibitor specific for all inflammatory caspases has been reported. Crystal structure of caspase-1 in complex with Ac-FLTD-CMK reveals extensive enzyme- inhibitor interactions involving both hydrogen bonds and hydrophobic contacts. Our ongoing studies of inflammatory caspases and inhibitors have elucidated the mechanisms for several lead compounds currently in clinical trials for liver diseases and epilepsy, and may have therapeutic potential for sepsis, multiple sclerosis, Alzheimer's disease, myocardial infarction, and AIDS.
Overall, progress made in the Xiao lab may reveal fundamental molecular mechanisms of innate immunity, and pave the way for targeting of inflammatory signaling pathways using small molecule compounds for diagnostic and therapeutic applications. As we embark on this exciting journey, we welcome applications from qualified and motivated individuals to join our team.
Yang, J., Liu, Z., Wang, C., Yang, R., Rathkey, J.K., Pinkard, O., Shi, W., Chen, Y., Dubyak, G.R., Abbott, D.W., and Xiao, T.S.: Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor. Proc. Natl. Acad. Sci. USA 115(26): 6792-6797, 2018. PMID: 29891674. PMCID: PMC6042100.
Liu, Z., Wang, C., Rathkey, J.K., Yang, J., Dubyak, G.R., Abbott, D.W., and Xiao, T.S.: Structures of the gasdermin D C-terminal domains reveal mechanisms of autoinhibition. Structure 26(5): 778-784, 2018. PMID: 29576317. PMCID: PMC5932255.
Li, Y., Huang, Y., Cao, X., Yin, X., Jin, X., Liu, S., Jiang, J., Jiang, W., Xiao, T.S., Zhou, R., Cai, G., Hu, B., Jin, T.: Functional and structural characterization of zebrafish ASC. FEBS J. 285(14): 2691-2707, 2018. PMID: 29791979. PMCID: PMC6105367.
Rathkey, J.K., Zhao, J., Liu, Z., Chen, Y., Yang, J., Kondolf, H.C., Benson, B.L., Chirieleison, S.M., Huang, A.Y., Dubyak, G.R., Xiao, T.S., Li, X., and Abbott, D.W.: Chemical disruption of the pyroptotic pore forming protein gasdermin D inhibits inflammatory cell death and sepsis. Science Immunology 3(26): eaat2738, 2018. PMID: 30143556.
Jin, T., Huang, M., Jiang, J., Smith, P., and Xiao, T.S.: Crystal structure of human NLRP12 PYD domain and implication in homotypic interaction. PLos One 13(1):e0190547, 2018. PMID:29293680. PMCID: PMC5749810.
Yangyuoru, P.M., Bradburn, D.A., Liu, Z., Xiao, T.S., and Russell, R.: The G-quadruplex (G4) resolvase DHX36 efficiently and specifically disrupts DNA G4s via a translocation-based helicase mechanism. Journal of Biological Chemistry 293(6): 1924-1932, 2018. PMID: 29269411. PMCID: PMC5808756.
Perez, J., Chen, Y., Xiao, T.S., and Abbott, D.W.: Phosphorylation of the E3 ubiquitin protein ligase ITCH diminishes binding to its cognate E2 ubiquitin ligase. Journal of Biological Chemistry 293(3): 1100-1105, 2018. PMID: 29212706. PMCID: PMC5777250.
Rathkey, J.K., Benson, B.L., Chirieleison, S.M., Yang, J., Xiao, T.S., Dubyak, G.R., Huang, A.Y., and Abbott, D.W.: Live cell visualization of gasdermin D driven pyroptotic cell death. Journal of Biological Chemistry 292(35): 14649-14658, 2017. PMID: 28726636. PMCID: PMC5582855.
Jin, T., Chuenchor, W., Jiang, J., Cheng, J., Li, Y., Fang, K., Huang, M., Smith, P., and Xiao, T.S.: Design of an expression system to enhance MBP-mediated crystallization. Scientific Reports 7:40991, 2017. PMID:28112203. PMCID: PMC5256280.
Yang, J., Liu, Z., and Xiao, T.S.: Post-translational regulation of the inflammasomes. Cellular & Molecular Immunology 14(1):65-79, 2017. PMID:27345727. PMCID: PMC5214939.
Xiao, T.S.: Innate immunity and inflammation. Cellular & Molecular Immunology 14(1):1-3, 2017. PMID:27545072. PMCID: PMC5214945.
Bertheloot, D., Horvath, G., Kolbeck, R., Naumovski, A., Langhoff, P., Garbi, N., Jin, T., Xiao, T.S., Latz, E.: RAGE enhances TLR responses through binding and internalization of RNA. Journal of Immunology 197(10):4118-4126, 2016. PMID:27798148. PMCID: PMC6062438.
Waldhuber, A., Snyder, G.A., Römmler, F., Cirl, C., Müller, T., Xiao, T.S., Svanborg, C., and Miethke, T.: A Comparative Analysis of the Mechanism of Toll-Like Receptor-Disruption by TIR-Containing Protein C from Uropathogenic Escherichia coli. Pathogens 5:25, 2016. PMID: 26938564. PMCID: PMC4810146.
Ni, C., Sy, M., Xiao, T.S., Tartakoff, A.M.: Polyglutamine tract expansion increases S-nitrosylation of Huntingtin and Ataxin-1. PLos One 11(9):e0163359, 2016. PMID:27658206. PMCID: PMC5033456.
Liu, Z. and Xiao, T. S.: Assembling the wheel of death. Science 350:376-377, 2015. PMID: 26494742. PMCID: PMC4668828.
Herzner, A., Hagmann, C.A., Goldeck, M., Wolter, S., Kübler, K., Wittmann, S., Gramberg, T., Andreeva, L., Hopfner, K., Mertens, C., Zillinger, T., Jin, T., Xiao, T.S., Bartok, E., Coch, C., Ackermann, D., Hornung, V., Ludwig, J., Barchet, W., Hartmann, G., and Schlee, M.: Sequence-specific activation of cGAS by Y-form DNA structures as found in primary HIV-1 cDNA. Nature Immunology 16:1025-1033, 2015. PMID:26343537. PMCID: PMC4669199.
Zhou, B., Jiang, J., Feng, H., Ghirlando, R., Xiao, T.S., and Bai, Y.: Structural mechanisms of nucleosome recognition by linker histones. Molecular Cell 59:628-638, 2015. PMID:26212454. PMCID: PMC4546531.
Mistry, P., Laird, M. H. W., Schwarz, R.S., Greene, S., Dyson, T., Snyder, G.A., Xiao, T.S., Chauhan, J., Fletcher, S., Toshchakov, V.Y., MacKerell, A.D., and Vogel, S.N.: Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain. Proc. Natl. Acad. Sci. USA, 112:5455-5460, 2015. PMID: 25870276. PMCID: PMC4418912.
Xiao, T.S.: The nucleic-acid sensing inflammasomes. Immunological Reviews 265: 103-111, 2015. PMID: 25879287. PMCID: PMC4364414.
Jin, T., and Xiao, T.S.: Activation and assembly of the inflammasomes through conserved protein domain families. Apoptosis 20:151-156, 2015. PMID: 25398536. PMCID: PMC4364414.
Chuenchor, W., Jin, T., Ravilious, G., and Xiao, T.S.: Structures of pattern recognition receptors reveal molecular mechanisms of autoinhibition, ligand recognition and oligomerization. Current Opinion in Immunology 26:14-20, 2014. PMID: 24419035. PMCID: PMC3944054.
Snyder, G. A. *, Deredge, D., Waldhuber, A., Fresquez, T., Wilkins, D.Z., Smith, P.T., Dürr, S., Cirl, C., Jiang, J., Jenning, W., Luchetti, T., Snyder, N., Sundberg, E.J., Wintrode, P., Miethke, T.*, and Xiao, T.S.*: Crystal structures of the TIR domains from the Brucella protein TcpB and host adapter TIRAP reveal mechanisms of molecular mimicry. Journal of Biological Chemistry 289:669-679, 2014. *Corresponding authors. PMID: 24275656. PMCID: PMC3887195.
Hong, J., Feng, H., Wang, F., Ranjan, A., Chen, J. Jiang, J., Ghirlando, R., Xiao, T.S., Wu, C., Bai, Y.: The catalytic subunit of the SWR1 remodeler is a histone chaperone for the H2A.Z-H2B dimer. Molecular Cell 53:498-505, 2014. PMID:24507717. PMCID: PMC3940207.
Abdi, K., Singh, N. J., Spooner, E., Kessler, B.M., Radaev, S. Lantz, L., Xiao, T.S., Matzinger, P., Sun, P.D., and Ploegh, H.L.: Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly. Journal of Immunology 192:6028-6036, 2014. PMID: 24821971. PMCID: PMC4070439.