My research, which is performed in close collaboration with Dr. Vojo Deretic, focuses on the autophagic targeting of HIV-1 by members of the TRIM family of proteins (TRIMs). 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. As detailed in a study published in Developmental Cell (August 2014), I found that TRIMs have dual roles in selective autophagy: as regulators and as cargo receptors. TRIM5α, a well-known anti-HIV restriction factor, promoted autophagy by acting as a platform for the assembly of autophagy initiation factors in their activated states. Furthermore, via interactions with both HIV-1 capsid and with proteins associated with autophagosome membranes, TRIM5α delivered HIV-1 for autophagic degradation. As part of my studies with TRIM5α, I found that many if not all TRIMs also regulate autophagy and have the capability to be selective autophagy receptors. As several TRIMs in addition to TRIM5α are known to protect cells against retroviral infection, my future studies will focus on testing the hypothesis that autophagy is their underlying mode of action in retroviral restriction.
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, Jain A, Choi SW, Mandell MA, Johansen T, Deretic V. TRIM-Directed Selective Autophagy Regulates Immune Activation. Autophagy. 2016 Mar 16:0. PMID: 26983397
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