Asa and Patricia Springer Professor of Structural Biology, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, USA
The ICIS Awards Committee have chosen Hao Wu, PhD as one of the two recipients of the 2019 Seymour & Vivian Milstein Award for Excellence in Interferon and Cytokine Research in recognition of her unparalleled contributions to the molecular mechanisms of cytokine signaling. Her in-depth mechanistic elucidation of many important protein complexes, in particular those used by the tumor necrosis factor receptor (TNFR) family, the Toll-like receptor/interleukin 1 receptor (TLR/IL-1R) family and the inflammasomes, not only changed how we understand cytokine-induced programmed cell death and immunity, but also presented a new paradigm for immune cell signaling.
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 Asa and Patricia Springer Professor of Structural biology in the Department 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, the Margaret Dayhoff Memorial Award from the Biophysical Society and most recently, the Dorothy Crowfoot Hodgkin Award from the Protein Society. She serves on the Scientific Advisory Council of the Cancer Research Institute and the Editorial Board of Cancer Cell.
Over two decades of research at Weill Cornell and Harvard, Hao has achieved an integrated understanding of protein signaling complexes generically denoted as “signalosomes”. She is internationally recognized for uncovering several fundamental themes in signal transduction of the immune system using structural biology approaches. Most notably, Hao revealed that, under physiological as well as pathological conditions, proteins of the death domain (DD) superfamily may assemble into higher-order structures with helical symmetry by a nucleated polymerization mechanism. She drew parallels between DD helical assembly and cytoskeletal filaments, and discovered that DD assembly is stabilized by three types of evolutionarily conserved protein-protein interactions. She then related these higher-order structures to their crucial signaling roles, where the assembly process concentrates signaling molecules such as caspases and kinases, rapidly amplifies signals, and mounts all-or-none threshold responses. Beyond providing structural and molecular basis for many key pathways in programmed cell death and immunity, her discoveries also spawn the development of therapeutics against diseases ranging from autoimmune disorders to cancer.
The following are a few studies highlighting Hao’s seminal research achievements:
To begin with, her lab provided insightful analysis on receptor-binding and ubiquitin ligase activity of TRAF proteins. She solved the first structure of a TRAF family member, TRAF2, and its complexes with peptides from a number of intracellular receptor tails and with TRADD (Park et al. Nature 1999; Ye et al. Molecular Cell, 2000; Park et al. Cell 2000). These structures not only revealed the trimeric structural architecture of TRAFs, but also defined sequence motifs for TRAF2 interaction that have been used widely by biologists to search for binding sites of TRAFs in proteins. She continued her work to TRAF6, a unique TRAF family member that is involved in the signaling of TLRs and IL-1Rs in addition to TNFRs. Her work identified a TRAF6-binding motif that is different from those used for TRAF2, and that is used widely for finding binding sites of TRAF6 in proteins (Ye et al., Nature 2002, Yin et al., NSMB 2009). TRAFs have RING domains that may serve as ubiquitin ligases. Her work illuminated the field by showing that only the RING domain of TRAF6, but not of TRAF2, can interact with E2 ubiquitin conjugating enzymes, rebutting an earlier misbelief in the field with regards to the ubiquitin ligase activity of TRAF2 (Yin et al. Biochemistry 2009). She further dissected the interaction between TRAF2 and cIAP1/cIAP2, suggesting that the apparent ubiquitin ligase activity of TRAF2 comes from the associated cIAP proteins (Zheng et al. Molecular Cell 2010).
On a second thread, her laboratory provided a rigorous and unprecedented detailed analysis of the Myddosome (MyD88-IRAK4-IRAK2) involved in TLR/IL-1R signaling (Lin et al., Nature 2010). The crystal structure of the Myddosome complex surprisingly reveals the helical, nucleated polymerization of DD proteins dictated by shape and electrostatic complementarity, which provides an elegant mechanism for signal transduction. Following this discovery, Hao’s group found that this assembly mechanism is also employed by inflammasomes (such as the NLRP3-ASC-Caspase-1 inflammasome), the intricate supramolecular complexes that are activated by diverse microbial and damage- associated signals to trigger immune response (Lu et al., Cell 2014). It turns out that nucleated polymerization is a unified mode of protein assembly and has far-reaching impacts in biology, as Hao’s laboratory elucidated with high-resolution structures of a death inducing signaling complex in apoptosis (Wang et al., NSMB 2010) and a signalosome in B-/T-cell receptor pathways (Qiao et al., Molecular Cell 2013). In more recent years, she uncovered how NLR-like proteins such as NLRC4 form inflammasomes using an ATPase-driving disk-like assembly architecture (Zhang et al., Science 2015), and she is now extending this mechanism to the NLRP3 inflammasome. Moving on from conventional signalosomes that function by recruiting downstream proteins, Hao now also investigates complexes that act as effectors of signalosomes. For instance, the recently identified gasdermin family mediates intercellular signaling by forming pores on the plasma membrane to allow cytokine release. To address the molecular mechanism of pore formation, Hao led her group to the functional characterization and structural determination of a gasdermin membrane pore (Ruan et al., Nature 2018), a study that significantly advanced the field of innate immunity.
Dr. Wu will accept her Milstein Award at Cytokines 2019 at the Awards Ceremony on Sunday, 20 October, 2019 at the Hofburg Congress Center in Vienna and give a talk in the Opening Session.