Michael Mandell's Laboratory

Vojo Deretic

Michael Mandell, Ph.D.

Assistant Professor
Molecular Genetics and Microbiology
MSC08 4660
1 University of New Mexico
Albuquerque, NM 87131-0001

Office: Fitz Hall, Room 351
Tel: (505) 504-0925

E-mail: mmandell@salud.unm.edu

Keywords: autophagy, TRIM5, HIV, AIDS, viral restriction

Research Interests:

My laboratory works to understand how autophagy, a fundamental process for cellular waste management, regulates inflammation and pathogenesis caused by the human immunodeficiency virus (HIV-1). We currently have two main projects related to achieving this goal.

Project #1: What is the role of autophagy in CD4+ T cell killing by HIV-1? HIV-1 infection leads to immunodeficiency by massively killing a key immune cell type known as CD4+ T cells. The depletion of these cells is a prerequisite for progression to AIDS. Interestingly, most of these CD4+ cells die as part of a cell-intrinsic immune response to HIV-1 DNA that builds up in cells when the viral life cycle is blocked. Work by our group and others has demonstrated that autophagy has anti-inflammatory properties resulting in part from its ability to sequester and degrade sources of inflammation or proteins involved in pro-inflammatory signaling. In this project, we seek to determine whether the anti-inflammatory properties of autophagy slows HIV-induced CD4+ T cell killing and if turning on autophagy could be an approach to mitigate HIV-1 pathogenesis. To address this question, we have established an ex vivo primary cell organoid HIV-1 infection model in which we can modulate autophagy through genetic or pharmacological means.

Project #2: How does the HIV-1 restriction factor TRIM5α engage autophagy in antiviral defense? The autophagy pathway can selectively target a wide variety of substrates for degradation. An important question is how these substrates are recognized. My studies of the TRIM family of proteins (TRIMs) answer this question. This protein family consists of more than 70 members in humans, with individual members affecting innate immunity, inflammation, and antiviral defense; although in most cases their mode of action has remained elusive. I found that most if not all TRIMs have dual roles in selective autophagy: as regulators and as cargo receptors. This is exemplified by HIV-1 restriction factor rhesus TRIM5α, which confers a potent and specific cross-species barrier that prevents HIV-1 from infecting rhesus macaques. TRIM5α promotes autophagy by acting as a platform for the assembly of autophagy initiation factors in their activated states. Furthermore, via direct interactions with both HIV-1 capsid and with proteins associated with autophagosome membranes, rhesus TRIM5α delivers HIV-1 for autophagic degradation. Our current studies seek to understand the roles of autophagy in TRIM5α action as a retroviral restriction factor, to understand how TRIM5α balances its pro-inflammatory and pro-autophagy functions, and to uncover the mechanistic details underlying TRIM actions in autophagy.

Other roles: Dr. Mandell is a founding member of the Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence (https://www.autophagy.center/). Dr. Mandell teaches in medical school classes (e.g. “Foundations of Medical Science: Immunology and Microbiology”, and “Infectious Diseases”) and in a variety of graduate level courses (e.g. “Molecular Virology”, “Microbial Pathogenesis”) and teaches a mini-course on introductory grant writing (Biomed505-007: Studying good proposals).

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Selected Publications

Link to Dr. Mandell's NCBI bibliography

Kehl SR, Soos BA, Choi SW, Herren AW, Johansen T, Mandell MA (2019). TAK1 converts Sequestosome 1/p62 from an autophagy receptor to a signaling platform.  EMBO Rep. 2019 Jul 25:e46238

Kumar S, Chauhan S, Jain A, Ponpuak M, Choi SW, Mudd M, Peters R, Mandell MA, Johansen T, Deretic V (2017). Galectins and TRIMs directly interact and orchestrate autophagic response to endomembrane damage. Autophagy. 2017 Jun 3;13(6):1086-1087. doi: 10.1080/15548627.2017.1307487. Epub 2017 Apr 3.

Mandell MA, Beverley SM (2017). Continual renewal and replication of persistent Leishmania major parasites in concomitantly immune hosts.  Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):E801-E810. doi: 10.1073/pnas.1619265114. Epub 2017 Jan 17.

Kimura T, Jain A, Choi SW, Mandell MA, Johansen T, Deretic V (2017).  TRIM-directed selective autophagy regulates immune activation.  Autophagy. 2017 May 4;13(5):989-990. doi: 10.1080/15548627.2016.1154254.

Chauhan S, Kumar S, Jain A, Ponpuak M, Mudd MH, Kimura T, Choi SW, Peters R, Mandell M, Bruun JA, Johansen T, Deretic V.  TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autphagy in Endomembrane Damage Homeostasis. Dev Cell. 2016 Oct 10;39(1):13-27. doi: 10.1016/j.devcel.2016.08.003.

Mandell MA, Jain A, Kumar S, Castleman MJ, Anwar T, Eskelinen EL, Johansen T, Prekeris R, Deretic V.  TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation.  J Cell Sci. 2016 Oct 1;129(19):3562-3573.

Mandell MA, Beverley SM. Concomitant immunity induced by persistent Leishmania major does not preclude secondary re-infection: implications for genetic exchange, diversity and vaccination.  PLoS Negl Trop Dis. 2016 Jun 28;10(6):e0004811. doi: 10.1371/journal.pntd.0004811.

Kimura T, Mandell M, Deretic V.  Precision autophagy directed by receptor regulators – emerging examples within the TRIM family.  J Cell Sci. 2016 Mar 1;129(5):881-91. doi: 10.1242/jcs.163758. Review.

Chauhan S, Ahmed Z, Bradfute SB, Arko-Mensah J, Mandell MA, Won Choi S, Kimura T, Blanchet F, Waller A, Mudd MH, Jiang S, Sklar L, Timmins GS, Maphis N, Bhaskar K, Piguet V, Deretic V.  Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential.  Nat Commun. 2015 Oct 27;6:8620. doi: 10.1038/ncomms9620.

Kimura T, Jain A, Choi SW, Mandell, MA, Schroder K, Johansen T, and V Deretic, 2015. TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J Cell Biol. Sep 7. PMID: 26347139

Chauhan S, Mandell, MA, and V Deretic, 2015. Mechanism of action of the tuberculosis and Crohn disease risk factor IRGM in autophagy. Autophagy. 2015 Aug 27. PMID: 26313894

Ponpuak M, Mandell, MA, Kimura T, Chauhan S, Cleyrat C, and V Deretic, 2015. Secretory Autophagy. Curr Opin Cell Biol. Aug;35:106-16. PMID: 25988755

Chauhan S, Mandell, MA, and V Deretic, 2014. IRGM governs the core autophagy machinery to conduct antimicrobial defense. Molecular Cell May 7;58(3):507-21. PMID: 25891078

Mandell, MA, Kimura T, Jain A, Johansen T, and V. Deretic V, 2014. TRIM proteins regulate autophagy: TRIM5 is a selective autophagy receptor mediating HIV-1 restriction. Autophagy. 2014;10(12):2387-8. PMID: 25587751

Mandell MA, Jain A, Arko-Mensah J, Chauhan S, Kimura T, Dinkins C, Silvestri G, Munch J, Kirchhoff F, Simonsen A, Wei Y, Levine B, Johansen T, Deretic V. TRIM Proteins Regulate Autophagy and Can Target Autophagic Substrates by Direct Recognition. Dev Cell. 2014 Aug 5. pii: S1534-5807(14)00402-X. doi: 10.1016/j.devcel.2014.06.013.

Bradfute, S.B., Castillo, E.F., Arko-Mensah, J., Chauhan, S., Jiang, S., Mandell, M.A., and V. Deretic, 2013. Autophagy as an immune effector against tuberculosis. Curr Opin Microbiol 16: 355-65. PMID: 23790398

Dokladny, K., Zuhl, M.N., Mandell, M.A., Bhattacharya, D., Schneider, S., Deretic, V., and P.L. Moseley. 2013. Regulatory coordination between two major intracellular homeostatic systems: heat shock response and autophagy. J Biol Chem 21:14959-72. PMID: 23576438

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.R., Dobos, K.M., and V. Deretic. 2012. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. PNAS 109:E3168-76. PMID: 23093667

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., and V. Deretic. 2012. TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity 37:223-34. PMID: 22921120

Vickers, TJ., Murta, S.M.F., Mandell, M.A., and S.M. Beverley, 2009. 10-Formyl-tetrahydrofolate synthesis occurs exclusively in the cytosol of the trypanosomatid parasite Leishmania major. Mol. Biochem. Parasitol 166:142-152. PMID: 19450731

Ng, L.G., Hsu, A., Mandell, M.A., Hoeller, C., Mrass. P., Iparraguirre, A., Cavanagh, L.L., Beverley, S.M., Scott, P., and W. Weninger, 2008. Migratory dermal dendritic cells act as rapid sensors of protozoan parasites. PLOS Pathogens 4: e100222. PMID: 19043558

Kelleher, J.F., Mandell, M.A., Moulder, G., Hill, K.L., L’Hernault, S.W., Barstead, R., and M.A. Titus, 2000. Myosin VI is required for asymmetric segregation of cellular components during C. elegans spermatogenesis. Current Biology 10:1489-1496. PMID: 11114515