Heads of Laboratories
Richard E. Salomon Family Associate Professor
Laboratory of Chemical Biology and Microbial Pathogenesis
The Hang laboratory is interested in elucidating fundamental mechanisms of host-microbe interactions and developing new therapeutic strategies to combat microbial infections.
Chemical tools for exploring metabolite-protein interactions. The emergence of microbial pathogens and adaptation of microbes to currently available drugs demands a better understanding of host-microbe interactions to prevent and treat infections. With the genetic blueprints of many microbes and animal hosts now available, new methods are needed to evaluate how key metabolites regulate host immunity and microbial virulence. To elucidate the mechanisms involved in host-microbe interactions, the Hang laboratory has developed robust chemical methods to image and profile the biochemical targets of metabolites in animal cells and microbes that are synthesized endogenously or derived from the environment (diet or microbiota). At the heart of this chemical approach is the design and synthesis of specific chemical reporters, metabolites bearing uniquely reactive groups, that can be chemically or enzymatically incorporated into biomolecules in vitro and in vivo and then selectively labeled with imaging or affinity purification reagents. Using this strategy, a variety of chemical reporters based on important metabolites (nucleosides, amino acids, lipids and other cofactors) have been developed in the Hang laboratory for the sensitive detection and analysis of metabolite-protein modifications such as palmitoylation, myristoylation, prenylation, acetylation, AMPylation, ADP-ribosylation as well as those derived from environmental metabolites such as flavonoids from medicinal plants.
Protein fatty-acylation in host immunity and microbial virulence. Metabolites from the diet, microbiota and cellular metabolism can significantly affect host susceptibility to infections. These active metabolites encompass a broad range of molecules ranging from fatty acids to bacterial cell well components. My laboratory has been especially focused on protein targets of long-chain fatty acids (LCFAs), since alterations in amounts and structure of LCFAs have profound effects on host immunity and pathogen susceptibility. For example, genetic defects in palmitic acid (C16:0) synthesis have been associated with impaired immune responses and resistance to infections. Conversely, high levels of palmitic acid from high-fat diets or adipocytes from obese animals have been suggested to activate immunity receptors and induce inflammation. These effects are specific to the structure of LCFAs, as unsaturated fatty acids such as oleic acid (C18:1) or pro-resolving lipid mediators such as resolvin and protectin facilitate the resolution of inflammatory responses and tissue repair. The balance of fatty acid levels and composition in animals is thus clearly very important in regulating appropriate immune responses, but the specific molecular targets and mechanisms by which LCFAs controls specific immune pathways are unclear.
Beyond essential functions in membrane biogenesis and metabolism, LCFAs can serve as ligands for specific receptors and also can be covalently attached to proteins (N-myristoylation, S-palmitoylation, Lys-fatty-acylation) and regulate their activity in membranes. While fatty acid binding to specific receptors can control some signaling pathways, these interactions are insufficient to explain the broad effects of LCFAs on inflammation and host susceptibility to infection. Indeed, chemical proteomic studies of immune cells in our laboratory have revealed many unpredicted fatty-acylated proteins involved in host immunity and pathogen susceptibility. These novel fatty-acylated proteins include IFITM-family proteins, which we first demonstrated are S-fatty-acylated on conserved Cys resides that are important for their membrane targeting and antiviral activity against influenza virus infection. Following our discovery of interferon-induced transmembrane protein 3 (IFITM3) S-fatty acylation-dependent antiviral activity, we are continuing to develop new approaches to characterize the precise mechanism of IFITM3 antiviral activity and its regulation by S-fatty-acylation that include 1) live cell imaging of IFITM3 during virus infection, 2) IFITM3-interactome studies and 3) in vitro reconstitution studies of recombinant and site-specifically lipidated IFITM3. These studies should help elucidate the precise mechanism of action for IFITM3, which is mutated in humans with increased morbidity and mortality to seasonal influenza A virus infections.
Discovery and development of anti-infective strategies. With dwindling supply of antibiotics and a growing appreciation for commensal microbes, new anti-infective strategies are needed to selectively target microbial pathogens without depleting the beneficial microbiota in humans. To develop new anti-infective approaches, the Hang laboratory is interested in understanding protective mechanisms of commensal bacteria and developing inhibitors of bacterial virulence pathways. While host-associated bacterial species have been shown to secrete metabolites and proteins for their beneficial affects, the mechanisms of action and targets of these commensal bacteria-derived molecules are not well understood and could lead to new anti-infective therapeutics. To identify new factors involved in host resistance or tolerance to pathogens, my laboratory has utilized Caenorhabditis elegans as a model system for exploring commensal bacteria and their secreted factors. We discovered that secreted antigen A (SagA) from Enterococcus faecium is sufficient to protect C. elegans against Salmonella pathogenesis by promoting pathogen tolerance. The NlpC/p60 peptidoglycan hydrolase activity of SagA is required and generated muramyl-peptide fragments that are sufficient to protect C. elegans against Salmonella pathogenesis in a tol-1-dependent manner. SagA can also be expressed and secreted to improve the protective activity of probiotics against Salmonella pathogenesis in mice. In collaboration with the Mucida Laboratory of Mucosal Immunology at Rockefeller, we showed that SagA-mediated protection mechanisms are conserved in mice and can be used to prevent enteric infections including C. difficile. These studies highlight how protective intestinal bacteria can modify microbial-associated molecular patterns to enhance pathogen tolerance and potentially be used enhance the activity of probiotics.
To complement the mechanistic studies of commensal bacteria, the Hang laboratory is also developing chemical inhibitors of key microbial virulence pathways to limit infections. Specifically, the Hang laboratory is working on small molecule inhibitors of type III secretion systems (T3SSs), which are responsible for injecting bacterial toxins and effector proteins into host cells and are essential for the virulence of many Gram-negative bacterial pathogens. Towards this goal, the Hang laboratory has developed a high-throughput assay for type III protein secretion and discovered and currently characterizing specific small molecules from medicinal plants and synthetic chemical libraries that can antagonize T3SSs and inhibit bacterial infection. Our recent studies on the type III protein secretion system (T3SS) inhibitors from medicinal plants, which suggests specific plant metabolites (flavonoids) covalently label and inactivate T3SS substrates to attenuate bacterial virulence (Tsou LK et al JACS 2016). These T3SS inhibitors are not broadly bactericidal and provide new lead compounds for selectively targeting bacterial pathogens responsible for disease without killing protective commensal bacteria. These studies highlight our ongoing efforts to discover and characterize new infective approaches to combat infections.
B.S. in chemistry, 1998
University of California, Santa Cruz
Ph.D. in chemistry, 2003
University of California, Berkeley
Harvard Medical School and Whitehead Institute for Biomedical Research, 2004–2006
Assistant Professor, 2007–2013
Associate Professor, 2013–
The Rockefeller University
Irma T. Hirschl/Monique Weill-Caulier Trust Research Award, 2007
Ellison Medical Foundation New Scholar Award, 2008
Grammel M, Hang HC. Chemical reporters for biological discovery. Nat. Chem. Biol. 9, 475–484 (2013).
Zhang M, Wu P-YJ, Kelly FD, Nurse P, Hang HC. Quantitative control of protein S-palmitoylation regulates meiotic entry in fission yeast. PLoS Biol. 11, e1001597 (2013).
Yount JS, Moltedo B, Yang YY, Charron G, Moran TM, López CB, Hang HC. Palmitoylome profiling reveals S-palmitoylation-dependent antiviral activity of IFITM3. Nat. Chem. Biol. 6, 610–604 (2010).
Rangan KJ, Pedicord VA, Wang Y-C, Kim B, Lu Y, Shaham S, Mucida D, Hang HC. A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens. Science 2016, 353, 1434-1437.
Tsou LK, Lara-Tejero M, RoseFigura J, Zhang ZJ, Wang YC, Yount JS, Lefebre M, Dossa PD, Kato J, Guan F, Lam W, Cheng YC, Galán JE, Hang HC. Antibacterial Flavonoids from Medicinal Plants Covalently Inactivate Type III Protein Secretion Substrates. J. Am. Chem. Soc. 2016, 138, 2209-18.
Dr. Hang is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Chemical Biology.