Vojo Deretic

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.

Vojo Deretic, PhD.
Known forAutophagy

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 HMGB1 and 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 area is still 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, excreted or released from cells.[9] 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.

Dr. Deretic's laboratory has furthermore linked autophagy with a large family of innate immunity proteins playing complex roles and termed TRIMs, such as TRIM5 (implicated in HIV restriction), TRIM16 and PYRIN/TRIM20 (implicated in inflammasome regulation), and TRIM21 (implicated in Type I Interferon responses) etc.[11] TRIMs play immune and other roles but with incompletely understood function(s), and the above cited work shows that they act 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] T[10]

A series of studies[15][16][17][18] from Dr. Deretic's group shows 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 downmstream of PRRs: NOD1, NOD2, TLRs, RIG-I and inflammasome components, enabling them to carry out antimicrobial and anti-inflammatory autophagic functions of significance in tuberculosis and Crohn's disease. A related line of studies shows that IRGM helps recruit a SNARE Syntaxin 17, which is also a target for phosphorylation and control by TBK1[19] and plays a role in both autophagy initiation and maturation. Both IRGM and Syntaxin 17 bind mammalain Atg8s such as MAP1LC3B (LC3s) and GABARAPs.[18] The most recnt studies[20] show that IRGM controls lysosomal biogenesis though binding to and controlling TFEB, the key transcriptional regulator of lysosomal genes. Moreover, mammalian Atg8s, which interact with IRGM, are upstream of lysosomal biogenesis and control both mTor and TFEB.[20] Thus, the notion that mammalain Atg8s, such as GABARAPs and LC3s, are builders of autophagsomal membrane may need to be revisited.

The mammalian Atg8s association with SNAREs has proven to be far more general than originally anticipated. It has recently been expanded to a large number of other SNAREs, with one specific subset characterized as driving lysosome biogenesis via a TGN-lysosome trafficking route.[21] These studies have led to an unanticipated alternative model for how mammalian Atg8s work - by broadly interacting with and modulating SNAREs to redirect general intracellular membrane flow toward the organelles that converge upon the lysosomal-autolysosomal system. Moreover, recent studies[20][22] show that mammalian Atg8s actually regulate lysosomal biogenesis, expanding or potentially revising their function that was originally restricted to be autophagosomal formation.

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,[23] this group has shown that a novel system termed GALTOR, based on Galectin-8, 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.[23] The physiological consequences of mTOR inhibition following endomembrane damage are many including induction of autophagy[23] and metabolic switching.

Dr. Deretic's group has previously shown how chloroquine works by functions in respiratory epithelial cells including suppressing inflammation and drivers of fibrosis that can lead to lung damage and loss of function,[24][25][26] and recently put that in the context of how chloroquine, azithromycin and ciprofloxacin may help with the covid19 pandemic crisis.[27] A follow-up study[28] indicates that ciprofloxacin has potent effects on inhibiting SARS-CoV-2 in Vero E6 cells as measured by reduced cytopathic effects, quantitative RT-PCR and plaque forming units. Ambroxol is another drug that has beneficial effects in Vero E6 cells.[28]

The functional roles of galectins in cellular response to membrane damage are rapidly expanding and Dr. Deretic's group has recently shown[29] that Galectin-3 recruits ESCRTs to damaged lysosomes so that lysosomes can be repaired. Most recent findings show that Galectin-9 responds to lysosomal damage by activating AMPK, a central regulator of metabolism and autophagy.[30] This occurs by Galectin-9-dependent activation of the ubiquitination systems on damaged lysosomes resulting in K63-ubiqutination of TAK1, an upstream kinase that phosphorylates and activates AMPK.[30]

A comprehensive review with over 1,000 citations 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 (the original discovery that autophagy acts against intracellular microbes with >2,000 citations) 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.

References

  1. Vojo, Deretic. "Autophagy, Inflammation and Metabolism (AIM) in Disease Center". Grantome.
  2. "AIM Center".
  3. 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 (6): 1–20. CiteSeerX 10.1.1.495.3789. doi:10.1016/j.cell.2004.11.038. PMID 15607973. S2CID 16651183.
  5. Castillo, E. F.; Dekonenko, A.; Arko-Mensah, J.; Mandell, M.A.; Dupont, N.; Jiang, S.; Delgado-Vargas, M.; Timmins, G.S.; Bhattacharya, D.; Yang, H.; Hutt, J.; Lyons, C.; Dobos, K. M.; Deretic, V. (2012). "Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation". Proc. Natl. Acad. Sci. USA. 109 (46): E3168–3176. doi:10.1073/pnas.1210500109. PMC 3503152. PMID 23093667.
  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. 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. 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. 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. PMC 6518167. 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 (4): 394–409. doi:10.1016/j.devcel.2014.06.013. PMC 4146662. PMID 25127057.
  13. 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 (6): 973–989. doi:10.1083/jcb.201503023. PMC 4576868. PMID 26347139.
  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 (5792): 1438–1441. Bibcode:2006Sci...313.1438S. doi:10.1126/science.1129577. PMID 16888103. S2CID 2274272.
  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 (12): 1154–1165. doi:10.1038/ncb2119. PMC 2996476. PMID 21102437.
  17. Chauhan, S.; Mandell, M.; Deretic, V. (2015). "IRGM Governs the Core Autophagy Machinery to Conduct Antimicrobial Defense". Molecular Cell. 58 (3): 507–521. doi:10.1016/j.molcel.2015.03.020. PMC 4427528. PMID 25891078.
  18. 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. 217 (3): 997–1013. doi:10.1083/jcb.201708039. ISSN 1540-8140. PMC 5839791. PMID 29420192.
  19. Kumar, Suresh; Gu, Yuexi; Abudu, Yakubu Princely; Bruun, Jack-Ansgar; Jain, Ashish; Farzam, Farzin; Mudd, Michal; Anonsen, Jan Haug; Rusten, Tor Erik; Kasof, Gary; Ktistakis, Nicholas (April 2019). "Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation". Developmental Cell. 49 (1): 130–144.e6. doi:10.1016/j.devcel.2019.01.027. ISSN 1534-5807. PMC 6907693. PMID 30827897.
  20. Kumar, Suresh; Jain, Ashish; Choi, Seong Won; da Silva, Gustavo Peixoto Duarte; Allers, Lee; Mudd, Michal H.; Peters, Ryan Scott; Anonsen, Jan Haug; Rusten, Tor-Erik; Lazarou, Michael; Deretic, Vojo (August 2020). "Mammalian Atg8 proteins and the autophagy factor IRGM control mTOR and TFEB at a regulatory node critical for responses to pathogens". Nature Cell Biology. 22 (8): 973–985. doi:10.1038/s41556-020-0549-1. ISSN 1465-7392. PMID 32753672. S2CID 220966510.
  21. Gu, Yuexi; Princely Abudu, Yakubu; Kumar, Suresh; Bissa, Bhawana; Choi, Seong Won; Jia, Jingyue; Lazarou, Michael; Eskelinen, Eeva‐Liisa; Johansen, Terje; Deretic, Vojo (2019-10-18). "Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s". The EMBO Journal. 38 (22): e101994. doi:10.15252/embj.2019101994. ISSN 0261-4189. PMC 6856626. PMID 31625181.
  22. Gu, Yuexi; Princely Abudu, Yakubu; Kumar, Suresh; Bissa, Bhawana; Choi, Seong Won; Jia, Jingyue; Lazarou, Michael; Eskelinen, Eeva‐Liisa; Johansen, Terje; Deretic, Vojo (2019-11-15). "Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s". The EMBO Journal. 38 (22). doi:10.15252/embj.2019101994. ISSN 0261-4189. PMC 6856626. PMID 31625181.
  23. 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. PMC 5911935. PMID 29625033.
  24. Poschet, J. F.; Boucher, J. C.; Tatterson, L.; Skidmore, J.; Van Dyke, R. W.; Deretic, V. (2001-11-20). "Molecular basis for defective glycosylation and Pseudomonas pathogenesis in cystic fibrosis lung". Proceedings of the National Academy of Sciences of the United States of America. 98 (24): 13972–13977. Bibcode:2001PNAS...9813972P. doi:10.1073/pnas.241182598. ISSN 0027-8424. PMC 61151. PMID 11717455.
  25. Ornatowski, Wojciech; Poschet, Jens F.; Perkett, Elizabeth; Taylor-Cousar, Jennifer L.; Deretic, Vojo (November 2007). "Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A-induced cytotoxicity". The Journal of Clinical Investigation. 117 (11): 3489–3497. doi:10.1172/JCI31499. ISSN 0021-9738. PMC 2030457. PMID 17948127.
  26. Perkett, Elizabeth A.; Ornatowski, Wojciech; Poschet, Jens F.; Deretic, Vojo (August 2006). "Chloroquine normalizes aberrant transforming growth factor beta activity in cystic fibrosis bronchial epithelial cells". Pediatric Pulmonology. 41 (8): 771–778. doi:10.1002/ppul.20452. ISSN 8755-6863. PMID 16779853.
  27. Deretic, Vojo; Timmins, Graham S (2020-03-31). "Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells". bioRxiv 10.1101/2020.03.29.008631.
  28. Timmins, Graham S; Bradfute, Steven B; Deretic, Vojo; Kumar, Suresh; Clarke, Elizabeth C; Ye, Chunyan (2020-08-11). "Ambroxol and Ciprofloxacin Show Activity Against SARS-CoV2 in Vero E6 Cells at Clinically-Relevant Concentrations". bioRxiv 10.1101/2020.08.11.245100.
  29. Jia, Jingyue; Claude-Taupin, Aurore; Gu, Yuexi; Choi, Seong Won; Peters, Ryan; Bissa, Bhawana; Mudd, Michal H.; Allers, Lee; Pallikkuth, Sandeep; Lidke, Keith A.; Salemi, Michelle (December 2019). "Galectin-3 Coordinates a Cellular System for Lysosomal Repair and Removal". Developmental Cell. 52 (1): 69–87.e8. doi:10.1016/j.devcel.2019.10.025. ISSN 1534-5807. PMC 6997950. PMID 31813797.
  30. Jia, Jingyue; Bissa, Bhawana; Brecht, Lukas; Allers, Lee; Choi, Seong Won; Gu, Yuexi; Zbinden, Mark; Burge, Mark R.; Timmins, Graham; Hallows, Kenneth; Behrends, Christian (January 2020). "AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System". Molecular Cell. 77 (5): 951–969.e9. doi:10.1016/j.molcel.2019.12.028. PMID 31995728.
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