Dr. Xiao graduated from Zhejiang University in China with a Bachelor's degree in Biological Sciences and Technology, and 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 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. He did 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 and adapter molecules implicated in antimicrobial host defense. Dr. Xiao joined the faculty at the Case Western Reserve University's Department of Pathology in 2014.
The Xiao lab uses structural and biochemical approaches to study important immune receptors with the goal of understanding and modulating their functions for diagnostic and therapeutic applications. Through collaborative efforts, we employ cellular assays and animal models to examine the roles of these receptors in immune defense against infections by Mycobacterium tuberculosis, HIV, vaccinia virus and HSV-1, as well as in autoimmune/autoinflammatory disorders such as systemic lupus erythematosus (SLE) and psoriasis. The innate immune system represents the first line of defense against microbial infection. Such protective role of the innate immune system relies on the proper function of the "sensor" molecules, the evolutionarily conserved pattern recognition receptors that recognize chemical signatures from microbes. Excessive activation of the pattern recognition receptors, however, can lead to highly inflammatory responses that cause tissue damage and autoimmune diseases.
Currently we are studying a number of cytosolic and cell surface receptors that mediate inflammatory immune responses to nucleic acids. A subset of the NLR and PYHIN family of innate immune receptors form large macromolecular signaling scaffolds known as the “inflammasomes,” a concept introduced by the late Jürg Tschopp in 2002. Inflammasomes are large signaling platforms composed of the receptors (such as NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4/NAIP, AIM2, and IFI16), the adapter protein ASC, and the effector enzyme procaspase-1. Activation of the inflammasomes leads to maturation of proinflammatory cytokines IL-1β and IL-18 and to a specific type of cell death named “pyroptosis.” Blocking IL-1 activities using FDA-approved drugs anakinra, rilonacept, and canakinumab has shown promise in the treatment of several inflammatory disorders, a testament to the physiological importance of the inflammasomes.
Our structural studies on the AIM2 inflammasome reveal the mechanisms of inflammasome activation through sequence-independent DNA recognition, the autoinhibition of the receptor via intramolecular domain-domain interactions, and the formation of the inflammasome through oligomerization at the multivalent DNA ligand. Building on our previous work, we are investigating mechanisms to modulate the functions of the AIM2 inflammasome and other immune receptors for the prevention and treatment of infections and autoimmune diseases. As we embark on this exciting journey, we welcome applications from qualified and motivated individuals to join our team.
Chuenchor, W., Jin, T., Ravilious, G., and Xiao, T.S. (2014). Structures of pattern recognition receptors reveal molecular mechanisms of autoinhibition, ligand recognition and oligomerization. Current Opinion in Immunology 26, 14–20.
Snyder, G.A., Deredge, D., Waldhuber, A., Fresquez, T., Wilkins, D.Z., Smith, P.T., Duerr, S., Cirl, C., Jiang, J., Jennings, W., et al. (2014). 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.
Hong, J., Feng, H., Wang, F., Ranjan, A., Chen, J., Jiang, J., Ghirlando, R., Xiao, T.S., Wu, C., and Bai, Y. (2014). The catalytic subunit of the SWR1 remodeler is a histone chaperone for the H2A.Z-H2B dimer. Molecular Cell 53, 498–505.
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. (2014). Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly. Journal of Immunology 192, 6028–6036.
Jakobsen, M.R., Bak, R.O., Andersen, A., Berg, R.K., Jensen, S.B., Jin, T., Laustsen, A., Hansen, K., Ostergaard, L., Fitzgerald, K.A., et al. (2013). IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication. Proc. Natl. Acad. Sci. U.S.A. 110, E4571–E4580.
Jin, T., Perry, A., Smith, P., Jiang, J., and Xiao, T.S. (2013). Structure of the Absent in Melanoma 2 (AIM2) Pyrin Domain Provides Insights into the Mechanisms of AIM2 Autoinhibition and Inflammasome Assembly. Journal of Biological Chemistry 288, 13225–13235.
, J., Burdette, D.L., Sharma, S., Bhat, N., Thompson, M., Jiang, Z., Rathinam, V.A.K., Monks, B., Jin, T., Xiao, T.S., et al. (2013). Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid. Journal of Immunology 190, 5216-5225.
Jin, T., Curry, J., Smith, P., Jiang, J., and Xiao, T.S. (2013). Structure of the NLRP1 caspase recruitment domain suggests potential mechanisms for its association with procaspase-1. Proteins: Structure, Function and Bioinformatics 81, 1266-1270.
Jin, T., Huang, M., Smith, P., Jiang, J., and Xiao, T.S. (2013). Structure of the caspase-recruitment domain from a zebrafish guanylate-binding protein. Acta Crystallographica F69, 855-860.
Kato, H., Jiang, J., Zhou, B.R., Rozendaal, M., Feng, H., Ghirlando, R., Xiao, T.S., Straight, A.F., and Bai, Y. (2013). A Conserved Mechanism for Centromeric Nucleosome Recognition by Centromere Protein CENP-C. Science 340, 1110–1113.
Latz, E., Xiao, T.S., and Stutz, A. (2013). Activation and regulation of the inflammasomes. Nature Reviews Immunology 13, 397–411.
Sirois, C.M., Jin, T., Miller, A.L., Bertheloot, D., Nakamura, H., Horvath, G.L., Mian, A., Jiang, J., Schrum, J., Bossaller, L., et al. (2013). RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. Journal of Experimental Medicine 210, 2447–2463.
Snyder, G.A., Cirl, C., Jiang, J., Chen, K., Waldhuber, A., Smith, P., Römmler, F., Snyder, N., Fresquez, T., and Dürr, S. (2013). Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic Escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 110, 6985–6990.
Jin, T., Huang, M., Smith, P., Jiang, J., and Xiao, T.S. (2013). Structure of the CARD8 caspase recruitment domain suggests its association with the FIIND domain and procaspases through adjacent surface. Acta Crystallographica F69, 482-487.
Xiao, T.S., and Fitzgerald, K.A. (2013). The cGAS-STING Pathway for DNA Sensing. Molecular Cell 51, 135–139.
Jin, T., Perry, A., Jiang, J., Smith, P., Curry, J.A., Unterholzner, L., Jiang, Z., Horvath, G., Rathinam, V.A., Johnstone, R.W., et al. (2012). Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36, 561–571.
Mu, R., Dussupt, V., Jiang, J., Sette, P., Rudd, V., Chuenchor, W., Bello, N.F., Bouamr, F., and Xiao, T.S. (2012). Two distinct binding modes define the interaction of Brox with the C-terminal tails of CHMP5 and CHMP4B. Structure 20, 887–898.
Xiao, T.S., and Ting, J.P.Y. (2012). NLRX1 Has a Tail to Tell. Immunity 36, 311–312.
Sette, P., Mu, R., Dussupt, V., Jiang, J., Snyder, G., Smith, P., Xiao, T.S., and Bouamr, F. (2011). The Phe105 loop of Alix Bro1 domain plays a key role in HIV-1 release. Structure 19, 1485–1495.
Unterholzner, L., Keating, S.E., Baran, M., Horan, K.A., Jensen, S.B., Sharma, S., Sirois, C.M., Jin, T., Latz, E., Xiao, T.S., et al. (2010). IFI16 is an innate immune sensor for intracellular DNA. Nature Immunology 11, 997–1004.
Xiao, T.S. (2010). Subversion of Innate Immune Signaling Through Molecular Mimicry. J Clinical Immunology 30, 638–642.
Xiao, T. (2008). Innate immune recognition of nucleic acids. Immunological Research 43, 98–108.
Zhu, J., Luo, B-H., Xiao, T., Zhang, C., Nishida, N., and Springer, T.A. (2008). Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Molecular Cell 32, 849-861.
Springer, T.A., Zhu, J., and Xiao, T. (2008). Structural basis for distinctive recognition of fibrinogen γC peptide by the platelet integrin αIIbβ3. Journal of Cell Biology 182, 791- 800.