Research

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Hao Wu, PhD

Hao Wu PhD
Lab:
Wu Laboratory
Program:
Program in Cellular and Molecular Medicine (PCMM)
Department:
Medicine Research
Division
Molecular Medicine Research
Hospital Title:
Senior Investigator
Academic Title:
Asa and Patricia Springer Professor, Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Harvard Medical School
Research Focus Area:
Immune Defense and Structural Biology
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Research Overview

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.

About Hao Wu

Dr. Wu received her pre-medical training at Peking University from 1982 to 1985 and studied Medicine at Peking Union Medical College from 1985 to 1988.  She obtained her Ph.D. degree in Biochemistry from Purdue University in 1992, working in the laboratory of Professor Michael Rossmann.  After performing postdoctoral training at Columbia University in the laboratory of Professor Wayne Hendrickson, she became an Assistant Professor at Weill Cornell Medical College in 1997 and was promoted to Professor in 2003.  In 2012, Dr. Wu moved to Harvard Medical School as the Springer Family Professor of Pediatrics, Professor of Biological Chemistry and Molecular Pharmacology, and Senior Investigator in the Program in Cellular and Molecular Medicine of Boston Children’s Hospital.  Dr. Wu has received a number of honors, including the Howard Hughes Medical Institute pre-doctoral fellowship, the Aaron Diamond postdoctoral fellowship, the Pew Scholar award, the Rita Allen Scholar award, New York Mayor’s Award for Excellence in Science and Technology, and the Margaret Dayhoff Memorial Award from the Biophysical Society.  She serves on the Scientific Advisory Council of the Cancer Research Institute and the Editorial Board of Cancer Cell.

Publications

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  1. Ru H, Chambers MG, Fu TM, Tong AB, Liao M, Wu H. Molecular Mechanism of V(D)J Recombination from Synaptic RAG1-RAG2 Complex Structures. Cell. 2015 Nov 19; 163(5):1138-52.
  2. Zhang L, Shuobing C, Jianbin R, Wu J, Tong AB, Yin Q, Li Y, David L, Lu A, Wang WL, Marks C, Ouyang Q, Zhang X, Mao Y, Wu H. Cryo-EM structure of the activated NAIP2/NLRC4 Inflammasome reveals nucleated polymerization. Science. 2015; 350:404-9.
  3. Ferrao R, Zhou H, Shan Y, Liu Q, Li Q, Shaw DE, Li X, Wu H. IRAK4 dimerization and trans-autophosphorylation are induced by Myddosome assembly. Mol Cell. 2014 Sep 18; 55(6):891-903.
  4. Qiao Q, Yang C, Zheng C, Fontán L, David L, Yu X, Bracken C, Rosen M, Melnick A, Egelman EH, Wu H. Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly. Mol Cell. 2013 Sep 26; 51(6):766-79.
  5. Wu H. Higher-order assemblies in a new paradigm of signal transduction. Cell. 2013 Apr 11; 153(2):287-92.
  6. 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.
  7. Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, Vos MR, Schröder GF, Fitzgerald KA, Wu H, Egelman EH. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell. 2014 Mar 13; 156(6):1193-206.
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