The Wu laboratory of mechanistic immunology focuses on elucidating the molecular mechanisms that govern the assembly, regulation and therapeutic intervention of supramolecular complexes in immunity, in particular innate immunity. Our current research focuses on inflammasomes, which are cellular machineries for activating inflammatory caspases. Activated caspases process the IL-1 family cytokines and the pore forming protein gasdermin D (GSDMD), and GSDMD pores release the mature cytokines and cause pyroptotic cell death. We also have ongoing projects on mechanism and therapeutic intervention in tumor necrosis factor (TNF) and Toll-like receptor (TLR) signaling pathways. There are three pillars for the research in the lab, 1) cryo-EM and other
biophysical methods for detailed understanding of molecular complexes, including a large number of membrane proteins, 2) drug screening and validation for potential therapeutics in immune diseases and cancer, and 3) cellular imaging and other tools for the assembly of supramolecular complexes in cells.
Boston Children's Hospital
3 Blackfan Circle
Boston MA 02115
Lab Size: Between 15 and 20
The Wu laboratory of structural immunology focuses on elucidating the molecular mechanism of signal transduction by immune receptors, especially innate immune receptors. The lab began its studies on the signaling of a classical cytokine produced by the innate immune system, tumor necrosis factor (TNF), which induces diverse cellular responses such as NF-κB activation and cell death. Receptors for TNF belong to the large TNF receptor (TNFR) superfamily. The second pursuit of the lab has been the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) superfamily, which induces signaling pathways overlapping with those of the TNFR superfamily. TLRs are transmembrane receptors that sense a discrete collection of molecules of microbial origin in the extracellular space and endosomes and members of IL-1R family are receptors for cytokines IL-1 and IL-18. TLRs and IL-1Rs share similar cytoplasmic domains. The lab recently expanded its research to a number of cytosolic pattern recognition receptors that provide intracellular surveillance of infections. Some of these intracellular sensors can induce pathways overlapping with those of TLRs such as activation of NF-κB and interferon regulatory factors. Others mediate the formation of inflammasomes that control activation of caspase-1, which in turn regulates maturation of the proinflammatory cytokines IL-1 and IL-18 and induces pyroptosis, a rapid inflammatory form of cell death.
The overall objective of the Wu lab has been to determine how macromolecular interactions mediate the transmission of signals from receptors to effectors to direct innate immune responses using the core approaches of structural biology. These structural studies challenge the traditional view of signal transduction as a string of recruitment and allosteric events. As a recurrent theme, the lab’s research revealed that upon ligand stimulation, many innate immune receptors assemble large oligomeric intracellular signaling complexes, or “signalosomes,” to induce the activation of caspases, kinases and ubiquitin ligases, leading to cell death, cytokine maturation or expression of gene products for immune and inflammatory responses. The different scaffolds identified by these structural studies provide a molecular foundation for understanding the formation of microscopically visible signaling clusters in cells.
Qian Yin, David P. Sester, Yuan Tian, Yu-Shan Hsiao, Alvin Lu, Jasmyn A. Cridlan, Vitaliya Sagulenko, Sara J. Thygesen, Divaker Choubey, Veit Hornung, Thomas Walz, Katryn J. Stacey, and Hao Wu. Molecular Mechanism for p202-mediated Specific Inhibition of AIM2 Inflammasome Activation. Cell Reports. 2013 Jul 9.
Wu H. Higher Order Assemblies in a New Paradigm of Signal Transduction. Cell. 2013 April 11. 153(2):287-292.
Yin Q, Tian Y, Kabaleeswaran V, Jiang X, Tu D, Eck MJ, Chen ZJ, Wu H. Cyclic di-GMP sensing via the innate immune signaling protein STING. Mol Cell. 2012 Jun 29;46(6):735-45.
Fontan L, Yang C, Kabaleeswaran V, Volpon L, Osborne MJ, Beltran E, Garcia M, Cerchietti L, Shaknovich R, Yang SN, Fang F, Gascoyne RD, Martinez-Climent JA, Glickman JF, Borden K, Wu H, Melnick A MALT1 Small Molecule Inhibitors Specifically Suppress ABC-DLBCL In Vitro and In Vivo Cancer Cell. 2012 Dec 11;22(6):812-24.
Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012 Jul 20;150(2):339-50