Investigation of microbiota mechanisms
Specific microbiota (bacteria, viruses, fungi) species can modulate host physiology, disease progression and response to therapy, but are challenging to mechanistically characterized. To elucidate the mechanisms of specific microbiota species, our laboratory has employed animal models (worms and mice), proteomics, metabolomics and developed new genetic methods to discover protective microbiota factors and characterize their mechanisms of action. Notably, we have discovered unique secreted NlpC/p60 peptidoglycan hydrolases from Enterococcus than can prime host immunity against infection.
PUBLICATIONS:
Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy. Griffin ME, Espinosa J, Becker JL, Luo JD, Carroll TS, Jha JK, Fanger GR, Hang HC. Science. 2021 Aug 27;373(6558):1040-1046. doi: 10.1126/science.abc9113.PMID: 34446607
RecT Recombinase Expression Enables Efficient Gene Editing in Enterococcuss. Chen V, Griffin ME, Maguin P, Varble A, Hang HC. Appl Environ Microbiol. 2021 Aug 26;87(18):e0084421. doi: 10.1128/AEM.00844-21. Epub 2021 Aug 26.PMID: 34232061
Enterococcus NlpC/p60 Peptidoglycan Hydrolase SagA Localizes to Sites of Cell Division and Requires Only a Catalytic Dyad for Protease Activity. Espinosa J, Lin TY, Estrella Y, Kim B, Molina H, Hang HC. Biochemistry. 2020 Nov 24;59(46):4470-4480. doi: 10.1021/acs.biochem.0c00755. Epub 2020 Nov 2.PMID: 33136372
Enterococcus faecium secreted antigen A generates muropeptides to enhance host immunity and limit bacterial pathogenesis. Kim B, Wang YC, Hespen CW, Espinosa J, Salje J, Rangan KJ, Oren DA, Kang JY, Pedicord VA, Hang HC. Elife. 2019 Apr 10;8:e45343. doi: 10.7554/eLife.45343.PMID: 30969170
Exploiting a host-commensal interaction to promote intestinal barrier function and enteric pathogen tolerance. Pedicord VA, Lockhart AAK, Rangan KJ, Craig JW, Loschko J, Rogoz A, Hang HC, Mucida D. Sci Immunol. 2016 Sep;1(3):eaai7732. doi: 10.1126/sciimmunol.aai7732. Epub 2016 Sep 22.PMID: 28580440
A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens. Rangan KJ, Pedicord VA, Wang YC, Kim B, Lu Y, Shaham S, Mucida D, Hang HC. Science. 2016 Sep 23;353(6306):1434-1437. doi: 10.1126/science.aaf3552. Epub 2016 Sep 22.PMID: 27708039
Chemical dissection of metabolites in infection and immunity
Metabolites from the environment (diet, microbiota, drugs) and host metabolism control diverse aspects of host physiology and disease, but their underlying mechanisms of action are still challenging to elucidate. To dissect key metabolite mechanisms in infection and immunity, our laboratory has developed innovative chemical tools and proteomic methods to discover the protein targets of key metabolites (short-chain fatty acids, peptidoglycan fragments, medicinal plant flavonoids and others) and to characterize their mechanisms of action.
PUBLICATIONS:
Chemoproteomics reveals microbiota-derived aromatic monoamine agonists for GPRC5A.
Zhao X, Stein KR, Chen V, Griffin ME, Lairson LL, Hang HC.Nat Chem Biol. 2023 May 29. doi: 10.1038/s41589-023-01328-z. Online ahead of print.PMID: 37248411
Anti-infective bile acids bind and inactivate a Salmonella virulence regulator.
Yang X, Stein KR, Hang HC. Nat Chem Biol. 2023 Jan;19(1):91-100. doi: 10.1038/s41589-022-01122-3. Epub 2022 Sep 29.PMID: 36175659
Translation of Microbiota Short-Chain Fatty Acid Mechanisms Affords Anti-infective Acyl-Salicylic Acid Derivatives. Yang X, Forster ER, Darabedian N, Kim AT, Pratt MR, Shen A, Hang HC. ACS Chem Biol. 2020 May 15;15(5):1141-1147. doi: 10.1021/acschembio.9b01009. Epub 2020 Mar 2.PMID: 32091869
Site-specific acylation of a bacterial virulence regulator attenuates infection. Zhang ZJ, Pedicord VA, Peng T, Hang HC. Nat Chem Biol. 2020 Jan;16(1):95-103. doi: 10.1038/s41589-019-0392-5. Epub 2019 Nov 18.PMID: 31740807
Peptidoglycan Metabolite Photoaffinity Reporters Reveal Direct Binding to Intracellular Pattern Recognition Receptors and Arf GTPases. Wang YC, Westcott NP, Griffin ME, Hang HC.ACS Chem Biol. 2019 Mar 15;14(3):405-414. doi: 10.1021/acschembio.8b01038. Epub 2019 Feb 20.PMID: 30735346
Antibacterial Flavonoids from Medicinal Plants Covalently Inactivate Type III Protein Secretion Substrates. 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. J Am Chem Soc. 2016 Feb 24;138(7):2209-18. doi: 10.1021/jacs.5b11575. Epub 2016 Feb 16.PMID: 26847396
Mechanisms of host immunity and microbial pathogenesis
To characterize fundamental mechanisms of host immunity, our laboratory has employed innovative chemical proteomics, live cell imaging, gene editing methods, as well as site-specific protein labeling and crosslinking methods to investigate host factors involved in microbial infections. In particular, we have investigated the antiviral mechanism(s) of interferon-induced transmembrane proteins (IFITMs) and their regulation by protein fatty-acylation. In addition, the chemical approaches we developed have facilitated mechanistic studies of microbial pathogenesis in collaboration with other laboratories.
PUBLICATIONS:
S-Palmitoylation and Sterol Interactions Mediate Antiviral Specificity of IFITMs.
Das T, Yang X, Lee H, Garst EH, Valencia E, Chandran K, Im W, Hang HC. ACS Chem Biol. 2022 Aug 19;17(8):2109-2120. doi: 10.1021/acschembio.2c00176. Epub 2022 Jul 21.PMID: 35861660
Site-Specific Lipidation Enhances IFITM3 Membrane Interactions and Antiviral Activity. Garst EH, Lee H, Das T, Bhattacharya S, Percher A, Wiewiora R, Witte IP, Li Y, Peng T, Im W, Hang HC. ACS Chem Biol. 2021 May 21;16(5):844-856. doi: 10.1021/acschembio.1c00013. Epub 2021 Apr 22.PMID: 33887136
Site-Specific Photo-Crosslinking Proteomics Reveal Regulation of IFITM3 Trafficking and Turnover by VCP/p97 ATPase. Wu X, Spence JS, Das T, Yuan X, Chen C, Zhang Y, Li Y, Sun Y, Chandran K, Hang HC, Peng T. Cell Chem Biol. 2020 May 21;27(5):571-585.e6. doi: 10.1016/j.chembiol.2020.03.004. Epub 2020 Apr 2.PMID: 32243810
IFITM3 directly engages and shuttles incoming virus particles to lysosomes. Spence JS, He R, Hoffmann HH, Das T, Thinon E, Rice CM, Peng T, Chandran K, Hang HC. Nat Chem Biol. 2019 Mar;15(3):259-268. doi: 10.1038/s41589-018-0213-2. Epub 2019 Jan 14.PMID: 30643282
Palmitoylome profiling reveals S-palmitoylation-dependent antiviral activity of IFITM3. Yount JS, Moltedo B, Yang YY, Charron G, Moran TM, López CB, Hang HC. Nat Chem Biol. 2010 Aug;6(8):610-4. doi: 10.1038/nchembio.405. Epub 2010 Jul 4.PMID: 20601941