Heads of Laboratories
Richard E. Salomon Family Assistant Professor
Laboratory of Chemical Biology and Microbial Pathogenesis
Howard.Hang@rockefeller.edu
Microbial pathogens have evolved sophisticated virulence mechanisms to subvert host defenses and cause disease. Dr. Hang is interested in developing chemical tools to understand how microbes evade host immune responses and identifying chemical inhibitors targeted at virulence pathways to combat microbial infections.
Bacterial pathogens and viruses remodel cellular membranes to infect host cells. To dissect the complex mechanisms by which microbial pathogens manipulate host membranes, the Hang laboratory has developed specific chemical reporters and bioorthogonal labeling methods to identify lipid-modified and membrane-associated proteins that are crucial for microbial infection of mammalian cells. Studies from the Hang laboratory have revealed that protein S-palmitoylation and S-prenylation control the membrane distribution and antimicrobial activity of several interferon-regulated proteins that confer host resistance to bacterial pathogens and viruses. In addition, the Hang laboratory has identified bacterial and viral protein effectors that are lipidated by host enzymes and targeted to membranes where they can antagonize host defense mechanisms during infection. These studies have revealed that protein lipidation is important for immunity as well as microbial virulence. The Hang laboratory continues to investigate microbial immune evasion mechanisms and is developing chemical reporters for other protein modifications (acetylation, prenylation and cholesteroylation) to explore their roles in microbial pathogenesis.
Given the importance of lipid-modified proteins in microbial pathogenesis, the Hang laboratory is investigating the basic mechanisms that control protein S-palmitoylation in eukaryotic cells. In particular, the Hang laboratory is taking advantage of the compact fission yeast genome to characterize the functions of protein acyltransferases and identify thioesterases that regulate dynamic S-palmitoylation in eukaryotes. These studies have revealed that transcriptional and posttranscriptional regulation of protein acyltransferases controls their substrate specificity towards S-palmitoylated proteins. Having demonstrated that fission yeast is a useful model organism for studying dynamic S-palmitoylation, the Hang laboratory is using chemical tools and fission yeast genetics to identify thioesterases that catalyze protein depalmitoylation. Dissecting the mechanisms that control protein S-palmitoylation is essential for understanding basic eukaryotic signaling pathways as well as the regulatory modifications of immune effectors and microbial virulence factors.
The establishment of robust chemical reporters and bioorthogonal labeling methods in the Hang laboratory also provides new opportunities to discover microbial virulence factors and vaccine candidates. For these studies the Hang laboratory is focusing on Salmonella, as serovars of this gram-negative intracellular bacterial pathogen are responsible for gastroenteritis as well as typhoid fever and are major causative agents of food- and water-borne diseases worldwide. For example, lipid and amino acid chemical reporters afford efficient tools for identifying bacterial lipoproteins and newly synthesized proteins that are uniquely expressed or secreted by Salmonella during infection of host cells. The functional roles of these uniquely expressed proteins in Salmonella virulence are ongoing in the Hang laboratory.
Finally, the Hang laboratory is interested in developing chemical inhibitors of microbial virulence mechanisms to treat infections. The injection of bacterial protein effectors into host cells through type III secretion systems (T3SSs) is essential for Salmonella invasion and replication. Furthermore, the needle complexes of T3SSs are conserved and crucial for the virulence of many gramnegative bacterial pathogens, making T3SSs attractive targets for antibacterial virulence inhibitors. Toward this goal, the Hang laboratory has developed a high throughput assay for type III protein secretion and discovered chemical inhibitors of T3SSs from medicinal plant extracts that block Salmonella infection of host cells. The discovery of plant metabolites that inhibit T3SSs provides lead compounds for the development of new antibacterial virulence drugs and raises interesting questions about how the plants interact with microbial pathogens in the environment.
CAREER
Dr. Hang received his undergraduate degree in chemistry from the University of California, Santa Cruz, in 1998 and his Ph.D. in chemistry from the University of California, Berkeley, in 2003. He was a postdoctoral fellow at Harvard Medical School and the Whitehead Institute for Biomedical Research. He joined Rockefeller in 2007 as assistant professor.
Dr. Hang received an Ellison Medical Foundation New Scholar Award in Aging in 2008 and an Irma T. Hirschl/Monique
Weill-Caulier Trust Research Award in 2007. He was awarded a Damon Runyon Cancer Research Foundation Postdoctoral
Fellowship in 2004.
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