Vojo Deretic

Vojo Deretic, PhD.
Known for Autophagy
Website www.autophagy.center

Vojo Deretic, Ph.D., is the director of the NIH-funded Autophagy, Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence.[1][2] The AIM center[2] aims to promote autophagy research nationally and internationally as well as to develop a cadre of junior faculty along with senior experts in this area to study fundamental mechanisms and how autophagy intersects with a broad spectrum of human disease and health states. Dr. Deretic is the departmental chair of the Department of Molecular Genetics and Microbiology as well as Professor of Molecular Genetics & Microbiology, Cell Biology & Physiology, and Neurology at the University of New Mexico.

Education

Vojo Deretic 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 University of New Mexico Health Sciences Center, in 2001.

Career & Research

Vojo Deretic's main contributions to science come from studies by his team on the role of autophagy in infection and immunity.[3] 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 [4] that autophagic degradation is a major effector of innate and possibly adaptive immunity mechanisms for direct elimination of intracellular microbes (such as Mycobacterium tuberculosis [5][6]). This has added immunity and infection to the repertoire of autophagy's sphere of influence.

The Deretic laboratory has subsequently 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 [7] including ferritin.[8] This has led to the term "secretory autophagy" [9][10] 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.

More recent studies in Dr. Deretic's laboratory show that a large family of proteins termed TRIMs, such as TRIM5, TRIM16, PYRIN/TRIM20, TRIM21, etc.[11] playing immune and other roles but with incompletely understood function(s), acts as autophagic receptor-regulators in mammalian cells.[8][12][13][14] Among these, TRIM16 has been proposed to play a role of the first selective secretory autophagy receptor.[13] This area is rapidly developing, which inevitably brings controversies such as gasdermin's role in IL-1 unconventional secretion via plasma membrane pores vs. secretory autophagy, and stimulates further work on a broad selection of substrates secreted or released from cells.[9][10]

A series of studies [15][16][17][18] 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 very recent study shows that IRGM helps recruit a SNARE Syntaxin 17 to autophagosome via mammalain Atg8s such as MAP1LC3B (LC3s) and GABARAPs.[18]

The most recent studies by Dr. Deretic's group from the AIM center for autophagy, inflammation and metabolism studies, provide insight into how cells detect endomembrane damage and what systems are deployed to help repair or eliminate/replace such membranes. In a recent paper in Molecular Cell,[19] this group has shown that a novel system termed GALTOR, based on galectins, interacts with the mTOR regulatory system composed of SLC38A9, Ragulator, RagA/B, RagCD. Following lysosomal damage, GALTOR inhibits mTOR causing its dissociation from damaged lysosomes. The key to GALTOR's action are galectins, sugar-binding cytosolic proteins, which can detect glycoconjugates exposed on the lumenal (exofacial) side of the lysosomal membrane upon membrane damage, thus transducing the breach of the membrane to mTOR.[19] The physiological consequences of mTOR inhibition following endomembrane damage are many including induction of autophagy [19] and metabolic switching.

A comprehensive review by Deretic and colleagues summarizes the role of autophagy in immunity and inflammation:[3] 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.

Some of the early publications include: Cell available here: (Gutierrez et al., 2004) http://www.cell.com/cell/fulltext/S0092-8674(04)01106-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867404011067%3Fshowall%3Dtrue and in Science available here: (Singh et al., 2006) http://science.sciencemag.org/content/313/5792/1438.

Several more recent primary publications include in Molecular Cell, available here: (Jia et al., 2018) http://www.cell.com/molecular-cell/fulltext/S1097-2765(18)30190-4 (Chauhan et al., 2015) http://www.cell.com/molecular-cell/abstract/S1097-2765%2815%2900211-7; in EMBO J, available here: (Dupont et al., EMBO J 2011) http://emboj.embopress.org/content/30/23/4701.long and here (Kimura et al., EMBO J 2017) http://emboj.embopress.org/content/36/1/42.long; in Developmental Cell, available here (Mandell et al., 2014) http://www.cell.com/developmental-cell/fulltext/S1534-5807(14)00402-X and here (Chauhan, Kumar et al., 2016) http://www.cell.com/developmental-cell/fulltext/S1534-5807(16)30568-8; and in J. Cell Biol., available here (Kimura et al., JCB 2015) http://jcb.rupress.org/content/210/6/973 and here (Kumar et al., JCB 2018) http://jcb.rupress.org/content/early/2018/02/01/jcb.201708039.

  • www.autophagy.center

References

  1. ↑ Vojo, Deretic,. "Autophagy, Inflammation and Metabolism (AIM) in Disease Center". Grantome.
  2. 1 2 "AIM Center".
  3. 1 2 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.
  4. ↑ 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. PMID 15607973.
  5. ↑ 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. "Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation." Proc. Natl. Acad. Sci. USA 109(46): E3168-3176 doi:10.1073/j.pnas.1210500109
  6. ↑ Deretic, V; Kimura, T; Timmins, G; Moseley, P; Chauhan, S; Mandell, M (Jan 2015). "Immunologic manifestations of autophagy". J Clin Invest. 125 (1): 75–84. doi:10.1172/JCI73945. PMC 4350422. PMID 25654553.
  7. ↑ Dupont, N; Jiang, S; Pilli, M; Ornatowski, W; Bhattacharya, D; Deretic, V (Nov 2011). "Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β". EMBO J. 30 (23): 4701–11. doi:10.1038/emboj.2011.398. PMC 3243609. PMID 22068051.
  8. 1 2 Kimura, Tomonori; Jia, Jingyue; Kumar, Suresh; Choi, Seong Won; Gu, Yuexi; Mudd, Michal; Dupont, Nicolas; Jiang, Shanya; Peters, Ryan (4 January 2017). "Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy". The EMBO Journal. 36 (1): 42–60. doi:10.15252/embj.201695081. ISSN 1460-2075. PMC 5210154. PMID 27932448.
  9. 1 2 Ponpuak, Marisa; Mandell, Michael A.; Kimura, Tomonori; Chauhan, Santosh; Cleyrat, Cédric; Deretic, Vojo (August 2015). "Secretory autophagy". Current Opinion in Cell Biology. 35: 106–116. doi:10.1016/j.ceb.2015.04.016. ISSN 1879-0410. PMC 4529791. PMID 25988755.
  10. 1 2 Claude-Taupin, Aurore; Jia, Jingyue; Mudd, Michal; Deretic, Vojo (2017-12-12). "Autophagy's secret life: secretion instead of degradation". Essays in Biochemistry. 61 (6): 637–647. doi:10.1042/EBC20170024. ISSN 1744-1358. PMID 29233874.
  11. ↑ Kimura, Tomonori; Mandell, Michael; Deretic, Vojo (2016-03-01). "Precision autophagy directed by receptor regulators - emerging examples within the TRIM family". Journal of Cell Science. 129 (5): 881–891. doi:10.1242/jcs.163758. ISSN 1477-9137. PMID 26906420.
  12. ↑ Mandell, M; Jain, A.; Arko-Mensah, J.; Chauhan, S.; Kimura, T.; Dinkins, C.; Silvestri, G; Münch, J.; Kirchhoff, F.; Simonsen, A.; Wei, Y.; Levine, B.; Johansen, T.; Deretic, V. (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.
  13. 1 2 Kimura, A. Jain A; Choi, S.W.; Mandell, M.A.; Schroder, K.; Johansen, T.; Deretic, V. (2015). "TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity". J. Cell Biol. 210: 973–989. doi:10.1083/jcb.201503023. PMC 4576868.
  14. ↑ Chauhan, Santosh; Kumar, Suresh; Jain, Ashish; Ponpuak, Marisa; Mudd, Michal H.; Kimura, Tomonori; Choi, Seong Won; Peters, Ryan; Mandell, Michael (10 October 2016). "TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis". Developmental Cell. 39 (1): 13–27. doi:10.1016/j.devcel.2016.08.003. ISSN 1878-1551. PMC 5104201. PMID 27693506.
  15. ↑ Singh, S.B.; Davis, A.; Taylor, G. A.; Deretic, V. (2006). "Human IRGM Induces Autophagy to Eliminate Intracellular Mycobacteria". Science. 313: 1438–1441. doi:10.1126/science.1129577. PMID 16888103.
  16. ↑ Singh, S. B.; Ornatowski, W.; Vergne, I.; Naylor, J.; Delgado, M.; Roberts, E.; Ponpuak, M.; Master, S.; Pilli, M.; White, E.; Komatsu, M.; Deretic, V. (2010). "Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria". Nat Cell Biol. 12: 1154–1165. doi:10.1038/ncb2119. PMC 2996476. PMID 21102437.
  17. ↑ Chauhan, S.; Mandell, M.; Deretic, V. "IRGM Governs the Core Autophagy Machinery to Conduct Antimicrobial Defense". Molecular Cell. 58: 507–521. doi:10.1016/j.molcel.2015.03.020. PMC 4427528.
  18. 1 2 Kumar, Suresh; Jain, Ashish; Farzam, Farzin; Jia, Jingyue; Gu, Yuexi; Choi, Seong Won; Mudd, Michal H.; Claude-Taupin, Aurore; Wester, Michael J. (2018-02-02). "Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins". The Journal of Cell Biology. doi:10.1083/jcb.201708039. ISSN 1540-8140. PMID 29420192.
  19. 1 2 3 Jia, Jingyue; Abudu, Yakubu Princely; Claude-Taupin, Aurore; Gu, Yuexi; Kumar, Suresh; Choi, Seong Won; Peters, Ryan; Mudd, Michal H.; Allers, Lee (2018-04-05). "Galectins Control mTOR in Response to Endomembrane Damage". Molecular Cell. 70 (1): 120–135.e8. doi:10.1016/j.molcel.2018.03.009. ISSN 1097-4164. PMID 29625033.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.