Faculty ProfilesMelanie Ott, MD, PhD
1650 Owens St
San Francisco, CA 94107
My laboratory is interested in the molecular mechanisms of viral pathogenesis. We focus on two viruses: HIV-1 and Hepatitis C Virus (HCV). Both are important public health problems and share common traits including high propensities to establish chronic infections and a lack of efficient vaccines. Our HIV efforts focus on viral transcription and latency as remaining barriers to viral eradication. We focus specifically on posttranslational modifications of the HIV transactivator Tat as potential targets to manipulate viral transcription therapeutically. In the past, we defined Tat acetylation and deacetylation as important steps in the Tat transactivation cycle and recently identified acetylation of the RNA polymerase II as an important regulatory step in transcription elongation. We are also interested in Tat-host cell interactions, specifically how Tat expression in infected T cells dysregulates immune functions and supports a premature aging syndrome observed in HIV+ individuals. Our HCV research focuses on the interaction of viral proteins with intracellular lipid droplets. These organelles play a critical role in the assembly of HCV progeny virions and are occupied in infected cells by the HCV nucleocapsid core. We recently showed that core interacts with the triglyceride-synthesizing enzyme DGAT1, and that this interaction plays a central role in the recruitment of core to lipid droplets. We are currently defining the role of lipid droplets in related viruses such as Dengue and Zika Virus and performed a comprehensive protein:protein interaction analysis of HCV proteins and hepatoma cells, which identified many novel factors involved in the infection. Both, HCV and HIV research in my laboratory includes replication studies with infectious viral clones, which are performed in the BSL3 laboratory. Recent rotation projects in the lab:
- defining the interaction of Dengue virus with lipid droplets
- characterizing a new posttranslational modification of Tat at lysine 71
- validating interaction partners of SIRT1 in T cells
Education and Training
|Location||Degree or Training||Specialty||Date|
|Picower Graduate School||Ph.D||1997|
|University of Frankfurt/Main||M.D||1991|
Recent Articles (56)
Jeng MY, Hull PA, Fei M, Kwon HS, Tsou CL, Kasler H, Ng CP, Gordon DE, Johnson J, Krogan N, Verdin E, Ott M. Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1. J Exp Med. 2018 Jan 02; 215(1):51-62.
Conrad RJ, Fozouni P, Thomas S, Sy H, Zhang Q, Zhou MM, Ott M. The Short Isoform of BRD4 Promotes HIV-1 Latency by Engaging Repressive SWI/SNF Chromatin-Remodeling Complexes. Mol Cell. 2017 Sep 21; 67(6):1001-1012.e6.
Boehm D, Jeng M, Camus G, Gramatica A, Schwarzer R, Johnson JR, Hull PA, Montano M, Sakane N, Pagans S, Godin R, Deeks SG, Krogan NJ, Greene WC, Ott M. SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency. Cell Host Microbe. 2017 May 10; 21(5):569-579.e6.
Besnard E, Hakre S, Kampmann M, Lim HW, Hosmane NN, Martin A, Bassik MC, Verschueren E, Battivelli E, Chan J, Svensson JP, Gramatica A, Conrad RJ, Ott M, Greene WC, Krogan NJ, Siliciano RF, Weissman JS, Verdin E. The mTOR Complex Controls HIV Latency. Cell Host Microbe. 2016 Dec 14; 20(6):785-797.
Khan S, Woodruff EM, Trapecar M, Fontaine KA, Ezaki A, Borbet TC, Ott M, Sanjabi S. Dampened antiviral immunity to intravaginal exposure to RNA viral pathogens allows enhanced viral replication. J Exp Med. 2016 Dec 12; 213(13):2913-2929.
Shirakawa K, Wang L, Man N, Maksimoska J, Sorum AW, Lim HW, Lee IS, Shimazu T, Newman JC, Schröder S, Ott M, Marmorstein R, Meier J, Nimer S, Verdin E. Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. Elife. 2016 05 31; 5.
Ali I, Ramage H, Boehm D, Dirk LM, Sakane N, Hanada K, Pagans S, Kaehlcke K, Aull K, Weinberger L, Trievel R, Schnoelzer M, Kamada M, Houtz R, Ott M. The HIV-1 Tat Protein Is Monomethylated at Lysine 71 by the Lysine Methyltransferase KMT7. J Biol Chem. 2016 07 29; 291(31):16240-8.
Lim HW, Kang SG, Ryu JK, Schilling B, Fei M, Lee IS, Kehasse A, Shirakawa K, Yokoyama M, Schnölzer M, Kasler HG, Kwon HS, Gibson BW, Sato H, Akassoglou K, Xiao C, Littman DR, Ott M, Verdin E. SIRT1 deacetylates ROR?t and enhances Th17 cell generation. J Exp Med. 2015 Jun 01; 212(6):973.
Lim HW, Kang SG, Ryu JK, Schilling B, Fei M, Lee IS, Kehasse A, Shirakawa K, Yokoyama M, Schnölzer M, Kasler HG, Kwon HS, Gibson BW, Sato H, Akassoglou K, Xiao C, Littman DR, Ott M, Verdin E. SIRT1 deacetylates ROR?t and enhances Th17 cell generation. J Exp Med. 2015 May 04; 212(5):607-17.
Ramage HR, Kumar GR, Verschueren E, Johnson JR, Von Dollen J, Johnson T, Newton B, Shah P, Horner J, Krogan NJ, Ott M. A combined proteomics/genomics approach links hepatitis C virus infection with nonsense-mediated mRNA decay. Mol Cell. 2015 Jan 22; 57(2):329-340.
Camus G, Schweiger M, Herker E, Harris C, Kondratowicz AS, Tsou CL, Farese RV, Herath K, Previs SF, Roddy TP, Pinto S, Zechner R, Ott M. The hepatitis C virus core protein inhibits adipose triglyceride lipase (ATGL)-mediated lipid mobilization and enhances the ATGL interaction with comparative gene identification 58 (CGI-58) and lipid droplets. J Biol Chem. 2014 Dec 26; 289(52):35770-80.
Schröder S, Herker E, Itzen F, He D, Thomas S, Gilchrist DA, Kaehlcke K, Cho S, Pollard KS, Capra JA, Schnölzer M, Cole PA, Geyer M, Bruneau BG, Adelman K, Ott M. Acetylation of RNA polymerase II regulates growth-factor-induced gene transcription in mammalian cells. Mol Cell. 2013 Nov 07; 52(3):314-24.
Vogt DA, Camus G, Herker E, Webster BR, Tsou CL, Greene WC, Yen TS, Ott M. Lipid droplet-binding protein TIP47 regulates hepatitis C Virus RNA replication through interaction with the viral NS5A protein. PLoS Pathog. 2013; 9(4):e1003302.
Camus G, Herker E, Modi AA, Haas JT, Ramage HR, Farese RV, Ott M. Diacylglycerol acyltransferase-1 localizes hepatitis C virus NS5A protein to lipid droplets and enhances NS5A interaction with the viral capsid core. J Biol Chem. 2013 Apr 05; 288(14):9915-23.
Kwon HS, Lim HW, Wu J, Schnölzer M, Verdin E, Ott M. Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J Immunol. 2012 Mar 15; 188(6):2712-21.
Boehm D, Calvanese V, Dar RD, Xing S, Schroeder S, Martins L, Aull K, Li PC, Planelles V, Bradner JE, Zhou MM, Siliciano RF, Weinberger L, Verdin E, Ott M. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle. 2013 Feb 01; 12(3):452-62.
Schröder S, Cho S, Zeng L, Zhang Q, Kaehlcke K, Mak L, Lau J, Bisgrove D, Schnölzer M, Verdin E, Zhou MM, Ott M. Two-pronged binding with bromodomain-containing protein 4 liberates positive transcription elongation factor b from inactive ribonucleoprotein complexes. J Biol Chem. 2012 Jan 06; 287(2):1090-9.
Sakane N, Kwon HS, Pagans S, Kaehlcke K, Mizusawa Y, Kamada M, Lassen KG, Chan J, Greene WC, Schnoelzer M, Ott M. Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog. 2011 Aug; 7(8):e1002184.
Herker E, Harris C, Hernandez C, Carpentier A, Kaehlcke K, Rosenberg AR, Farese RV, Ott M. Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med. 2010 Nov; 16(11):1295-8.
Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, Meyers D, Cole PA, Ott M, Gan L. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010 Sep 23; 67(6):953-66.
Pagans S, Kauder SE, Kaehlcke K, Sakane N, Schroeder S, Dormeyer W, Trievel RC, Verdin E, Schnolzer M, Ott M. The Cellular lysine methyltransferase Set7/9-KMT7 binds HIV-1 TAR RNA, monomethylates the viral transactivator Tat, and enhances HIV transcription. Cell Host Microbe. 2010 Mar 18; 7(3):234-44.
Cho S, Schroeder S, Kaehlcke K, Kwon HS, Pedal A, Herker E, Schnoelzer M, Ott M. Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells. EMBO J. 2009 May 20; 28(10):1407-17.
Kwon HS, Brent MM, Getachew R, Jayakumar P, Chen LF, Schnolzer M, McBurney MW, Marmorstein R, Greene WC, Ott M. Human immunodeficiency virus type 1 Tat protein inhibits the SIRT1 deacetylase and induces T cell hyperactivation. Cell Host Microbe. 2008 Mar 13; 3(3):158-67.
Mahmoudi T, Parra M, Vries RG, Kauder SE, Verrijzer CP, Ott M, Verdin E. The SWI/SNF chromatin-remodeling complex is a cofactor for Tat transactivation of the HIV promoter. J Biol Chem. 2006 Jul 21; 281(29):19960-8.
Pagans S, Pedal A, North BJ, Kaehlcke K, Marshall BL, Dorr A, Hetzer-Egger C, Henklein P, Frye R, McBurney MW, Hruby H, Jung M, Verdin E, Ott M. SIRT1 regulates HIV transcription via Tat deacetylation. PLoS Biol. 2005 Feb; 3(2):e41.
Ott M, Dorr A, Hetzer-Egger C, Kaehlcke K, Schnolzer M, Henklein P, Cole P, Zhou MM, Verdin E. Tat acetylation: a regulatory switch between early and late phases in HIV transcription elongation. Novartis Found Symp. 2004; 259:182-93; discussion 193-6, 223-5.
Kaehlcke K, Dorr A, Hetzer-Egger C, Kiermer V, Henklein P, Schnoelzer M, Loret E, Cole PA, Verdin E, Ott M. Acetylation of Tat defines a cyclinT1-independent step in HIV transactivation. Mol Cell. 2003 Jul; 12(1):167-76.
Schwer B, North BJ, Frye RA, Ott M, Verdin E. The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol. 2002 Aug 19; 158(4):647-57.
Dorr A, Kiermer V, Pedal A, Rackwitz HR, Henklein P, Schubert U, Zhou MM, Verdin E, Ott M. Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain. EMBO J. 2002 Jun 03; 21(11):2715-23.