Heinrich Gottlinger MD, PhD
Title | Professor |
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Institution | University of Massachusetts Medical School |
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Department | Molecular, Cell and Cancer Biology |
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Address | University of Massachusetts Medical School 364 Plantation Street, LRB-526 Worcester MA 01605
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Phone | 508-856-2843 |
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Institution | UMMS - School of Medicine |
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Department | Biochemistry and Molecular Pharmacology |
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Institution | UMMS - School of Medicine |
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Department | Molecular, Cell and Cancer Biology |
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Institution | UMMS - School of Medicine |
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Department | Program in Molecular Medicine |
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Institution | UMMS - Graduate School of Biomedical Sciences |
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Department | Biochemistry and Molecular Pharmacology |
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Institution | UMMS - Graduate School of Biomedical Sciences |
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Department | Immunology and Virology |
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Institution | UMMS - Graduate School of Biomedical Sciences |
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Department | Interdisciplinary Graduate Program |
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Biography Thomas-Mann Gymnasium, Munich, , Germany | BS | | Science | Ludwig Maximilian University of Munich, Munich, , Germany | MD | | Medicine | Ludwig Maximilian University of Munich, Munich, , Germany | PH D | | Philosophy |
Overview Academic BackgroundHeinrich Gottlinger received his M.D. from the University of Munich in 1983. From 1984 to 1989 he was a post-doctoral fellow, first at the Institute of Immunology, University of Munich, and later at the Dana-Farber Cancer Institute in Boston, where his work was funded by a stipend from the German Research Council. He became a faculty member in the Department of Pathology at Harvard in 1991, where he remained until he joined the Program in Gene Function and Expression at the University of Massachusetts Medical School in September of 2004. Dr. Gottlinger is the recipient of a National Institutes of Health Merit Award. Molecular Biology of HIV-1 The overall goal of the lab is to understand at the molecular level how an infectious HIV-1 virus particle is formed and what cellular proteins are involved.
HIV-1 particle assembly and budding are driven by the viral Gag protein, which contains specific domains that are absolutely required for the virus to detach from the host cell. Towards the goal of understanding the function of these “late assembly” domains, we recently identified AIP1 as a cellular binding partner involved in HIV-1 budding. AIP1 is a component of the cellular class E vacuolar protein sorting (Vps) machinery, which normally functions in an endosomal budding pathway that is conserved from yeast to man. Our results indicate that AIP1 serves to link the late assembly domains of HIV-1 and other lentiviruses to a large endosomal sorting complex called ESCRT-III. Remarkably, the release of HIV-1 and various other enveloped viruses is completely blocked in the presence of defective ESCRT-III components. We are currently using a combination of siRNA knockdown and mutagenesis techniques to determine how the assembly of the ESCRT-III complex is regulated, and how AIP1 and ESCRT-III facilitate virus budding. Additionally, we use HIV as a model system to elucidate how the human class E Vps machinery functions in protein sorting and vesicular transport. We also study the role of Nef, a virulence factor of HIV-1 that is crucial for rapid progression to AIDS. Nef increases the intrinsic infectivity of HIV-1 progeny virions, but the mechanism is not understood. Our recent results show that Nef binds to a key regulator of endocytosis, which is required for the ability of Nef to increase viral infectivity. Since our results suggest that Nef down-modulates a cellular factor that restricts HIV-1 infectivity, we have used a high-resolution proteomics approach to compare the global protein content of wild type and mutant HIV-1 virions. This approach has yielded a number of cellular proteins that are selectively incorporated into HIV-1 particles in a manner that depends on a specific viral structural or regulatory protein. The viral binding sites for these cellular proteins are currently being mapped, and the results will be used to construct and analyze HIV-1 mutants that lack these sites. To complement and validate these virological studies, we will use knockdown approaches to directly examine the relevance of specific host factors for the HIV-1 life cycle. We expect that these studies will provide insights not only into the function of Nef, but also into the mechanism of virus release, virus spreading via cell-to-cell transmission, and the unique ability of lentiviruses such as HIV-1 to infect non-dividing, terminally differentiated cells.
Potential Rotation Projects1.The identification of novel binding partners for cellular proteins required for HIV-1 budding using a double tag immunoaffinity purification approach. 2.The characterization of mutant ESCRT-III components that block HIV-1 budding with regard to subcellular localization and their ability to interact with certain phosphoinositol lipids and with other proteins involved in late endosomal sorting. 3.The mapping of binding sites for cellular proteins that we have identified as specific components of HIV-1 using GST pulldown, yeast two-hybrid, and co-immunoprecipitation approaches. 4.The generation and functional characterization of mutant viral Gag proteins that fail to interact with specific cellular partners. A postdoctoral position is available to study in this laboratory. Contact Dr. Gottlinger for additional details. Bibliographic
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications.
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Weissenhorn W, Miguet N, Aschman N, Renesto P, Usami Y, Gottlinger HG. Structural basis of tetherin function. Curr HIV Res. 2012 Jun; 10(4):298-306. PMID: 22524178.
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Martinelli N, Hartlieb B, Usami Y, Sabin C, Dordor A, Miguet N, Avilov SV, Ribeiro EA, Göttlinger H, Weissenhorn W. CC2D1A is a regulator of ESCRT-III CHMP4B. J Mol Biol. 2012 May 25; 419(1-2):75-88. PMID: 22406677.
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Solomons J, Sabin C, Poudevigne E, Usami Y, Hulsik DL, Macheboeuf P, Hartlieb B, Göttlinger H, Weissenhorn W. Structural basis for ESCRT-III CHMP3 recruitment of AMSH. Structure. 2011 Aug 10; 19(8):1149-59. PMID: 21827950.
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Weiss ER, Göttlinger H. The role of cellular factors in promoting HIV budding. J Mol Biol. 2011 Jul 22; 410(4):525-33. PMID: 21762798.
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Göttlinger HG. Influenza exits the cell without an ESCRT. Cell. 2010 Sep 17; 142(6):839-41. PMID: 20850005.
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Weiss ER, Popova E, Yamanaka H, Kim HC, Huibregtse JM, Göttlinger H. Rescue of HIV-1 release by targeting widely divergent NEDD4-type ubiquitin ligases and isolated catalytic HECT domains to Gag. PLoS Pathog. 2010 Sep 16; 6(9):e1001107. PMID: 20862313.
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Popova E, Popov S, Göttlinger HG. Human immunodeficiency virus type 1 nucleocapsid p1 confers ESCRT pathway dependence. J Virol. 2010 Jul; 84(13):6590-7. PMID: 20427536.
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Hinz A, Miguet N, Natrajan G, Usami Y, Yamanaka H, Renesto P, Hartlieb B, McCarthy AA, Simorre JP, Göttlinger H, Weissenhorn W. Structural basis of HIV-1 tethering to membranes by the BST-2/tetherin ectodomain. Cell Host Microbe. 2010 Apr 22; 7(4):314-23. PMID: 20399176.
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Pires R, Hartlieb B, Signor L, Schoehn G, Lata S, Roessle M, Moriscot C, Popov S, Hinz A, Jamin M, Boyer V, Sadoul R, Forest E, Svergun DI, Göttlinger HG, Weissenhorn W. A crescent-shaped ALIX dimer targets ESCRT-III CHMP4 filaments. Structure. 2009 Jun 10; 17(6):843-56. PMID: 19523902.
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Popov S, Popova E, Inoue M, Göttlinger HG. Divergent Bro1 domains share the capacity to bind human immunodeficiency virus type 1 nucleocapsid and to enhance virus-like particle production. J Virol. 2009 Jul; 83(14):7185-93. PMID: 19403673.
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Calistri A, Del Vecchio C, Salata C, Celestino M, Celegato M, Göttlinger H, Palù G, Parolin C. Role of the feline immunodeficiency virus L-domain in the presence or absence of Gag processing: involvement of ubiquitin and Nedd4-2s ligase in viral egress. J Cell Physiol. 2009 Jan; 218(1):175-82. PMID: 18792916.
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Pizzato M, Popova E, Göttlinger HG. Nef can enhance the infectivity of receptor-pseudotyped human immunodeficiency virus type 1 particles. J Virol. 2008 Nov; 82(21):10811-9. PMID: 18715908.
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Lata S, Schoehn G, Jain A, Pires R, Piehler J, Gottlinger HG, Weissenhorn W. Helical structures of ESCRT-III are disassembled by VPS4. Science. 2008 Sep 5; 321(5894):1354-7. PMID: 18687924.
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Lata S, Roessle M, Solomons J, Jamin M, Gottlinger HG, Svergun DI, Weissenhorn W. Structural basis for autoinhibition of ESCRT-III CHMP3. J Mol Biol. 2008 May 9; 378(4):818-27. PMID: 18395747.
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Javanbakht H, Halwani R, Cen S, Saadatmand J, Musier-Forsyth K, Gottlinger H, Kleiman L. The interaction between HIV-1 Gag and human lysyl-tRNA synthetase during viral assembly. J Biol Chem. 2003 Jul 25; 278(30):27644-51. PMID: 12756246.
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Cowan S, Hatziioannou T, Cunningham T, Muesing MA, Gottlinger HG, Bieniasz PD. Cellular inhibitors with Fv1-like activity restrict human and simian immunodeficiency virus tropism. Proc Natl Acad Sci U S A. 2002 Sep 3; 99(18):11914-9. PMID: 12154227.
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Strack B, Calistri A, Accola MA, Palu G, Gottlinger HG. A role for ubiquitin ligase recruitment in retrovirus release. Proc Natl Acad Sci U S A. 2000 Nov 21; 97(24):13063-8. PMID: 11087860.
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Romeo F, Cilento N, Scoppa GF, Anania C, Maffei G, Prato R. Combined curietherapy and surgery in management of stage II.B cervical carcinoma. Eur J Gynaecol Oncol. 1990; 11(6):473-6. PMID: 2086231.
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Lever A, Gottlinger H, Haseltine W, Sodroski J. Identification of a sequence required for efficient packaging of human immunodeficiency virus type 1 RNA into virions. J Virol. 1989 Sep; 63(9):4085-7. PMID: 2760989.
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Fogler WE, Klinger MR, Abraham KG, Gottlinger HG, Riethmuller G, Daddona PE. Enhanced cytotoxicity against colon carcinoma by combinations of noncompeting monoclonal antibodies to the 17-1A antigen. Cancer Res. 1988 Nov 15; 48(22):6303-8. PMID: 2460221.
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Year | Publications |
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1988 | 1 | 1989 | 1 | 1990 | 1 | 2000 | 1 | 2002 | 1 | 2003 | 1 | 2008 | 3 | 2009 | 3 | 2010 | 4 | 2011 | 2 | 2012 | 2 |
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