Research

Research priorities: Innate immunity, inflammation, pyroptosis, immunogenic cell death, bacterial infection

Feng Shao has discovered a series of cytosolic innate immune receptors for major bacterial products (like LPS) as well as the downstream pyroptosis executioner gasdermin-D (GSDMD). These original contributions lay out the foundation for understanding how our body recognizes and defends against various pathogenic bacterial infections in the cytosol space. His further identification of the Gasdermin family of pore-forming proteins re-defines the concept of pyroptosis, thereby opening a new area in cell death, inflammation and immunity.

Central to the immune system is the sensing of pathogen infection. Toll-like receptors (TLRs) recognize extracellular bacteria and stimulate cytokine production, but little was known about how bacteria are detected in the cytosol. Feng Shao has identified several pattern recognition receptors (PRRs) for invading bacterial pathogens/toxins. These include the NAIP family for bacterial flagellin and type III secretion apparatus, and Pyrin (encoded by the familial Mediterranean fever gene) that senses various bacterial toxins. He has also showed that caspase-4/5 in humans and caspase-11 in mice are intracellular receptors for bacterial LPS. In addition, he has uncovered that ADP-heptose, a precursor of LPS biosynthesis, is recognized by a host kinase ALPK1 and stimulates NF-κB-mediated proinflammatory responses, therefore revealing another way through which LPS is sensed by host immune system. This series of landmark discoveries establish a framework about cytosolic antibacterial immunity.

Cytosolic immune receptors often activate pyroptosis, but the mechanism was unknown for 20 years. Shao has solved the mystery by identifying the GSDMD protein, whose cleavage and activation by caspase-1 and caspase-4/5/11 determines pyroptosis. He further found that GSDMD has a membrane pore-forming activity that directly executes pyroptosis and also mediates the release of caspase-1-processed IL-1β. Shao’s findings raise a novel concept that systemic pyroptosis activated by the intracellular LPS-sensing pathway determines sepsis.

Shao has further discovered that the large gasdermin family are all pyroptosis-inducing factors, redefining pyroptosis as gasdermin-mediated programmed necrosis. His work shows that GSDME is cleaved and activated by caspase-3 and therefore switches apoptosis to pyroptosis. The finding has overturned the dogma that caspase-3 activation is a marker for apoptosis, and changed our understanding about the role of caspases in programmed cell death.

Career

• since 2014 Deputy Director for Academic Affairs, National Institute of Biological Sciences, Beijing, China
• since 2012 Investigator, National Institute of Biological Sciences, Beijing, China
• 2009-2012 Associate investigator, National Institute of Biological Sciences, Beijing, China
• 2005-2009 Assistant investigator, National Institute of Biological Sciences, Beijing, China
• 2004-2005 Damon Runyon Postdoctoral Fellow, Harvard Medical School, Boston, MA, USA
• 2003 Postdoctoral research fellow, University of California, San Diego, CA, USA
• 1999-2003 PhD in Biological Chemistry, University of Michigan, Ann Arbor, MI, USA
• 1996-1999 MS in Molecular Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
• 1991-1996 BS in Applied Chemistry, Peking University, Beijing, China

Functions

• since 2020 Member of the External Advisory Board (EAB) of UCL Great Ormond Street Institute of Child Health
• since 2020 Editorial board, Cell Host and Microbe
• since 2020 Associate editor, Science Advances
• since 2019 Editorial board, PLOS Biology
• since 2019 Member and consultant, the Roche Immunology Incubator Board
• 2019-2021 Hong Kong Research Grants Council (RGC) Biology and Medicine Panel Member
• since 2018 Member of the China National Committee of Science and Technology Awards
• since 2018 Vice president, The Chinese Society of Biochemistry and Molecular Biology (CSBMB)
• since 2018 Board of Directors, The Chinese Biological Investigator Society (CBIS)
• since 2017 Council Member, China National Postdoctoral Science Foundation
• since 2017 Scientific advisor, the Life Science Division of the Natural Science Foundation of China
• 2015-2018 Board of Directors, The Ray Wu Memorial Fund
• 2012-2018 Board of Reviewing Editors, eLife
• since 2012 Editor, Cellular Microbiology

Projects

• 2018-2022 NSFC Basic Science Center Project on “Innate immunity and inflammatory diseases” (#81788101)
• 2016-2022 China Ministry of Science and Technology Key Research and Development Plan Project on “Protein machinery in regulation of biological processes” (#2016YFA0501500)
• 2014-2017 The Program for International Collaborations between NSFC and ISC (Israel Science Foundation) on “Pathogen sensing by epithelial cells: the enteropathogenic E. coli paradigm” (#31461143006)
• 2012-2018 The Strategic Priority Research Program of the Chinese Academy of Sciences on “Protein Machinery” (#XDB08020202)

Honours and Memberships

• 2019 Future Science Prize – Life Sciences
• 2019 Qiu Shi Outstanding Scientist Award
• since 2019 Member of the German National Academy of Sciences Leopoldina
• since 2016 Elected Fellow of American Academy of Microbiology
• since 2015 Elected Member of the Chinese Academy of Sciences
• since 2015 Elected Associate Member of the EMBO
• 2014 The Wu Jieping-Paul Janssen Medical & Pharmaceutical Award
• 2013 The Protein Society Young Investigator Award (formally The Irving Sigal Young Investigator Award)
• 2012-2016 Howard Hughes Medical Institute (HHMI), International Early Career Award