Areas of Specialty

The goal of the Mandell laboratory is to understand how cells coordinate responses to intracellular threats with a focus on retroviral infection. In particular, we study members of the TRIM family of proteins. There are more than 70 TRIMs in the human genome, many of which function to protect cells from viral infection. As antiviral molecules, TRIMs can both directly interfere with viral life cycles and can function as key regulators of innate immunity. Our studies revealed a novel, yet highly conserved, action of TRIMs in another cytoprotective pathway: autophagy. Autophagy is a degradative pathway responsible for the removal of unnecessary and/or potentially dangerous cytoplasmic contents including viruses. Autophagy also has emerging roles in controlling innate immunity. We have shown that TRIMs can control when the cell ‘turns on’ autophagy and can also determine which cellular components are selectively targeted for autophagic removal. Thus, TRIM proteins are positioned as the ‘ringleaders’ of cellular antiviral and innate immune functions. We are working to uncover how TRIMs coordinate these actions.

Our current studies are focused on the HIV-1 restriction factor TRIM5. We have shown that TRIM5 biochemically interacts with multiple components of the autophagy machinery and assembles them into functional complexes. We recently connected these autophagy-related functions of TRIM5 to its actions in antiviral defense. We found that TRIM5 leverages the autophagy machinery to promote antiviral signaling and the establishment of a broadly antiviral state. In this setting, we identified a novel role for the autophagy machinery in scaffolding the assembly of active TRIM5 signaling structures which is in contrast the typical degradative actions of the autophagy pathway.

We are using cell biological, immunological, and proteomic approaches to understand the mechanisms underlying how autophagy contributes to TRIM5’s actions in transducing antiviral signaling. We anticipate that these experiments will advance our understanding of how cells respond to viral infection and reveal novel functions of TRIM5 while also enabling an improved understanding of how autophagy works in mammalian cells.  

Key Publications

Saha B, Chisholm D, Kell AM, Mandell MA (2020) A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α. PLoS Pathog 16(10): e1009017. https://doi.org/10.1371/journal.ppat.1009017

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

Courses Taught

Dr. Mandell is co-block chair of the medical school Immunology and Microbiology block, participates 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).

Research and Scholarship

Dr. Mandell is a founding member of the Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence.