Vojo Deretic

Vojo Deretic, Ph.D., is Professor of Molecular Genetics & Microbiology and Cell Biology & Physiology at the University of New Mexico He received his undergraduate, graduate and postdoctoral education in Belgrade, Paris, and Chicago. He was a faculty member at the University of Texas, University of Michigan, and joined the Department of Molecular Genetics and Microbiology, University of New Mexico, in 2001. Dr. Deretic has served for many years as a permanent member on National Institutes of Health study sections and on panels for other funding agencies including the Cystic Fibrosis Foundation, and was Chair of the NIH AIDS Opportunistic Infections and Cancer (AOIC) study section. He is a member of the Faculty of 1000, serves on editorial boards of several journals, and has over 180 peer-reviewed publications.^[1] In July 2006, Dr. Deretic was appointed Chair of the Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine.

Vojo Deretic's main contributions to science come from studies by his team on the role of autophagy in infection and immunity.^[2] Autophagy, a cytoplasmic pathway for the removal of damaged or surplus organelles, has been previously implicated in cancer, neurodegeneration such as Alzheimer's disease, Huntington's disease and Parkinson's disease, diabetes, development, and aging. His group is one of those that made the discovery ^[3] that autophagic degradation is a major effector of innate and possibly adaptive immunity mechanisms for direct elimination of intracellular microbes (such as Mycobacterium tuberculosis ^[4][5]).

The Deretic laboratory has shown that autophagy in mammalian cells plays not only a degradative role but that it also carries the task of unconventional secretion of cytoplasmic proteins, such as IL-1beta and others.^[6] These proteins normally reside in the cytosol but exert their functions extracellularly. This work, along with the work by others in yeast, extends the influence sphere of autophagy from its canonical roles inside the cell and the confines of the intracellular space to the extracellular space, affecting cell-cell interactions, inflammation, tissue organization, function, and remodeling.

The latest studies in Dr. Deretic's laboratory show that a large family of proteins termed TRIMs, playing immune and other roles but with incompletely understood function(s), acts as autophagic receptor-regulators in mammalian cells.^[7] TRIMs organize autophagic machinery in mammalian cells to carry out a highly selective or "precision" autophagy of their targets. For example, TRIM5, a restriction factor against HIV, organizes autophagic apparatus and recognizes and delivers retroviral capsid proteins for destruction in autophagosomes.^[8] The concept of precision autophagy, whereby receptors recognize specific targets and assemble core autophagy factors to initiate autophagic degradation has been extended by the definition of TRIM20 (PYRIN) and TRIM21 as receptor-regulators for removal of inflammasome components and type I interferon regulators, respectively, via precision autophagy.^[9]

A series of earlier studies ^[10][11] and the most recent study ^[12] from Dr. Deretic's group show how the human immunity related GTPase IRGM works in autophagy by demonstrating IRGM's direct interactions with the core autophagy (ATG) factors, and their assembly and activation enabling them to carry out antimicrobial and anti-inflammatory autophagic functions of significance in tuberculosis and Crohn's disease.

A comprehensive review by Deretic and colleagues summarizes the role of autophagy in immunity and inflammation: Deretic, V., T. Saitoh, S. Akira. 2013. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 13:722-37. http://www.nature.com/nri/journal/v13/n10/abs/nri3532.html.

The most recent primary publications: in Molecular Cell (May 2015) available here: http://www.cell.com/molecular-cell/abstract/S1097-2765%2815%2900211-7 ; in J. Cell Biol. (September 2015), available here: http://jcb.rupress.org/content/210/6/973.

Publications

• Gutierrez, M. G.; Master, S. S.; Singh, S. B.; Taylor, G. A.; Colombo, M. I.; Deretic, V. (2004). "Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages". Cell. 119: 1–20. doi:10.1016/j.cell.2004.11.038. 
• Singh, S.B., A. Davis, G. A. Taylor, and V. Deretic. 2006. Human IRGM Induces Autophagy to Eliminate Intracellular Mycobacteria. Science 3 August 2006: 11295771 doi:10.1126/science.1129577
• Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol. 2013 Oct;13(10):722-37.http://www.nature.com/nri/journal/v13/n10/abs/nri3532.html.
• Mandell, M, A. Jain, J. Arko-Mensah, S. Chauhan, T. Kimura, C. Dinkins, Silvestri, G, J. Münch, F. Kirchhoff, A. Simonsen, Y. Wei, B. Levine, T. Johansen, V. Deretic. 2014. TRIM Proteins Regulate Autophagy and Can Target Autophagic Substrates by Direct Recognition. Developmental Cell. 30:394-409. doi:10.1016/j.devcel.2014.06.013
• S. Chauhan, M. Mandell and V. Deretic. 2015. IRGM Governs the Core Autophagy Machinery to Conduct Antimicrobial Defense. Molecular Cell. doi:10.1016/j.molcel.2015.03.020.

§Harris, J., S. A. De Haro, S. S. Master, J. Keane, E., A. Roberts, M. Delgado, and V. Deretic. 2007. T helper 2 cytokines inhibit autophagic control of intracellular M. tuberculosis. Immunity, 27:505-517. §Levine B and Deretic. 2007. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 7:767-77. §Deretic, V., and D. J. Klionsky. 2008. How cells clean house. Scientific American 298:74-81. §Delgado-Vargas, M.A., Elmaoued, R.A., David, A.S., Kyei, G., and Deretic, V. 2008. Toll-like receptors control autophagy. EMBO J., 27(7): 1110-21. §Kyei, G.B., Dinkins, C., Davis, A.S., Roberts, E., Singh, S.B., Dong, C., Wu, L., Kominami, E., Ueno, T., Yamamoto, A., Federico, M., Panganiban, A., §Vergne, I., and Deretic., V. 2009. Autophagy pathway intersects with HIV-1 biogenesis and regulates viral yields in macrophages. J Cell Biol 186:255-68. §Deretic, V., and Levine, B. (2009). Autophagy, Immunity, and Microbial Adaptations. Cell Host and Microbe 5:527-549. §Vergne, I., E. Roberts, R.E. Elmaoued, V. Tosch, M. A Delgado, T. Proikas-Cézanne, J. Laporte and V. Deretic. (2009) Control of autophagy initiation by phosphoinositide 3-phosphatase Jumpy. EMBO J. 28:2244-2258. §Deretic, V. 2010. Autophagy in infection. Current opinion in cell biology 22:252-262. §Ponpuak, M., Davis, A.S., Roberts, E.A., Delgado, M.A., Dinkins, C., Zhao, Z., Virgin, H.W.t., Kyei, G.B., Johansen, T., Vergne, I., and Deretic, V. 2010. Delivery of cytosolic components by autophagic adaptor protein p62 endows autophagosomes with unique antimicrobial properties. Immunity 32:329-341. §Singh, S. B., W. Ornatowski, I. Vergne, J. Naylor, M. Delgado, E. Roberts, M. Ponpuak, S. Master, M. Pilli, E. White, M. Komatsu, and V. Deretic. 2010. Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria. Nat Cell Biol 12:1154-1165. §Dupont, N., Jiang, S., Pilli, M., Ornatowski, W., Bhattacharya, D., and Deretic, V. 2011. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1beta. Embo J 30:4701-4711. §Deretic, V. 2012. Autophagy: an emerging immunological paradigm. J Immunol 189:15-20. §Deretic, V., S. Jiang, and N. Dupont. 2012. Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation. Trends Cell Biol 22:397-406. §Deretic, V. 2012. Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors. Curr Opin Immunol 24:21-31.

• Pilli, M.; Arko-Mensah, J.; Ponpuak, M.; Roberts, E.; Master, S.; Mandell, M. A.; Dupont, N.; Ornatowski, W.; Jiang, S.; Bradfute, S. B.; Bruun, J. A.; Hansen, T. E.; Johansen, T.; Deretic, V. (2012). "TBK-1 Promotes Autophagy-Mediated Antimicrobial Defense by Controlling Autophagosome Maturation". Immunity. 37: 223–234. doi:10.1016/j.immuni.2012.04.015. 
• Castillo, E. F., A. Dekonenko, J. Arko-Mensah, M.A. Mandell, N. Dupont, S. Jiang, M. Delgado-Vargas, G.S. Timmins, D. Bhattacharya, H. Yang, J. Hutt, C. Lyons, K. M. Dobos, V. Deretic. 2012.
• Deretic V, Kimura T, Timmins G, Moseley P, Chauhan S, Mandell M. Immunologic manifestations of autophagy. J Clin Invest. 2015 Jan;125(1):75-84. doi:10.1172/JCI73945. Epub 2015 Jan 2.PMID 25654553.

References