Research Departments & Organizations
Exploring how a cell consumes itself -- Macroautophagy is classically defined as a pathway for the nonspecific sequestration and degradation of cytosolic material when the cell is faced with persistent starvation. This cytosolic material is captured within a double-membraned vesicle (the autophagosome) which forms de novo and ultimately traffics the material to the lysosome for degradation (and release of valuable nutrients). However, this pathway can also be utilized as a stress response to a wide variety of specific cellular insults. The ability to capture and degrade specific cytoplasmic targets including protein aggregates, invading pathogens or even whole dysfunctional organelles forms the basis of the cell’s response to diseases ranging from neurodegeneration to cancer and heart disease. In each case, large cytoplasmic targets are identified and encapsulated newly-formed autophagosomes for delivery to the lysosome. How these targets are identified and how this organelle forms are the major foci of our laboratory.
Specialized Terms: Macroautophagy; Autophagy
Extensive Research Description
Faced with persistent starvation, the cell can “consume itself”. Macroautophagy is a pathway for the sequestration and ultimate delivery of cytosol to the lysosome for degradation and release of valuable nutrients. Interestingly, the same pathway can be highjacked to selectively dispose of cytosolic toxins ranging from protein inclusions to dying organelles, and thus macroautophagy has been linked to a range of diseases (neurodegeneration, heart disease, cancer, viral infection, etc.). However, despite this widespread translational interest, fundamental questions remain unanswered.
We are studying how the cell forms, de novo, a new organelle (the autophagosome) to sequester free cytosol. In particular, we are interested in what membranes are harvested for this purpose, how the autophagosome grows, how cargo is targeted to these membranes and how the cell carries out potentially complex membrane dynamics and intracellular fusion to effect the formation of the unique double-membrane structure of the autophagosome. Ultimately we expect that protein function and membrane architecture will be revealed by combining low resolution cell-based assays with high resolution imaging (electron cryo-microscopy) of both isolated organelles and reconstituted autophagosome mimetics, vesicles imbued with all the detail we currently possess about autophagosome proteomic character.
ATG2 transports lipids to promote autophagosome biogenesis.
Valverde DP, Yu S, Boggavarapu V, Kumar N, Lees JA, Walz T, Reinisch KM, Melia TJ. ATG2 transports lipids to promote autophagosome biogenesis. The Journal Of Cell Biology 2019, 218:1787-1798. 2019
Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes.
Lystad AH, Carlsson SR, de la Ballina LR, Kauffman KJ, Nag S, Yoshimori T, Melia TJ, Simonsen A. Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes. Nature Cell Biology 2019, 21:372-383. 2019
Maturation and Clearance of Autophagosomes in Neurons Depends on a Specific Cysteine Protease Isoform, ATG-4.2.
Hill SE, Kauffman KJ, Krout M, Richmond JE, Melia TJ, Colón-Ramos DA. Maturation and Clearance of Autophagosomes in Neurons Depends on a Specific Cysteine Protease Isoform, ATG-4.2. Developmental Cell 2019, 49:251-266.e8. 2019
Delipidation of mammalian Atg8-family proteins by each of the four ATG4 proteases.
Kauffman KJ, Yu S, Jin J, Mugo B, Nguyen N, O'Brien A, Nag S, Lystad AH, Melia TJ. Delipidation of mammalian Atg8-family proteins by each of the four ATG4 proteases. Autophagy 2018, 14:992-1010. 2018
Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3.
Nath S, Dancourt J, Shteyn V, Puente G, Fong WM, Nag S, Bewersdorf J, Yamamoto A, Antonny B, Melia TJ. Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. Nature Cell Biology 2014, 16:415-24. 2014
The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation.
Choy A, Dancourt J, Mugo B, O'Connor TJ, Isberg RR, Melia TJ, Roy CR. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science (New York, N.Y.) 2012, 338:1072-6. 2012
SNARE proteins are required for macroautophagy.
Nair U, Jotwani A, Geng J, Gammoh N, Richerson D, Yen WL, Griffith J, Nag S, Wang K, Moss T, Baba M, McNew JA, Jiang X, Reggiori F, Melia TJ, Klionsky DJ. SNARE proteins are required for macroautophagy. Cell 2011, 146:290-302. 2011
Acetylation-Dependent Clearance of Soluble Mutant Huntingtin by Autophagy
Jeong H., Then F., Melia, T., Mazzulli, J.R., Cui, L., Savas, J.N., Voisine, C., Tanese N., Hart A.C., Yamamoto, A. and Krainc, D. 2009. Acetylation-Dependent Clearance of Soluble Mutant Huntingtin by Autophagy. Cell 137, 60-72. 2009
Selective activation of cognate SNAREpins by Sec1/Munc18 proteins.
Shen J, Tareste DC, Paumet F, Rothman JE, Melia TJ. Selective activation of cognate SNAREpins by Sec1/Munc18 proteins. Cell 2007, 128:183-95. 2007