Thomas Melia, PhD
Research & Publications
Biography
News
Research Summary
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.
Coauthors
Research Interests
Autophagy; Cell Biology; Lysosomes; Phagosomes; Protein Aggregates
Selected Publications
- LC3B is lipidated to large lipid droplets during prolonged starvation for noncanonical autophagyOmrane M, Ben M'Barek K, Santinho A, Nguyen N, Nag S, Melia T, Thiam A. LC3B is lipidated to large lipid droplets during prolonged starvation for noncanonical autophagy. Developmental Cell 2023 PMID: 37315562, DOI: 10.1016/j.devcel.2023.05.009.
- ATG9 vesicles comprise the seed membrane of mammalian autophagosomesOlivas T, Wu Y, Yu S, Luan L, Choi P, Guinn E, Nag S, De Camilli P, Gupta K, Melia T. ATG9 vesicles comprise the seed membrane of mammalian autophagosomes. Journal Of Cell Biology 2023, 222: e202208088. PMID: 37115958, PMCID: PMC10148236, DOI: 10.1083/jcb.202208088.
- Functionalized DNA-Origami-Protein Nanopores Generate Large Transmembrane Channels with Programmable Size-SelectivityShen Q, Xiong Q, Zhou K, Feng Q, Liu L, Tian T, Wu C, Xiong Y, Melia T, Lusk C, Lin C. Functionalized DNA-Origami-Protein Nanopores Generate Large Transmembrane Channels with Programmable Size-Selectivity. Journal Of The American Chemical Society 2022, 145: 1292-1300. PMID: 36577119, PMCID: PMC9852090, DOI: 10.1021/jacs.2c11226.
- Closing the autophagosome is easy‐PCFuller D, Melia T. Closing the autophagosome is easy‐PC. The EMBO Journal 2022, 42: e113046. PMID: 36478568, PMCID: PMC9841321, DOI: 10.15252/embj.2022113046.
- ATG9 Vesicles Are Incorporated Into Nascent Autophagosome MembranesOlivas T, Yu S, Wu Y, Luan L, Choi P, Gupta K, De Camilli P, Melia T. ATG9 Vesicles Are Incorporated Into Nascent Autophagosome Membranes. The FASEB Journal 2022, 36 DOI: 10.1096/fasebj.2022.36.s1.0r457.
- Atg39 selectively captures inner nuclear membrane into lumenal vesicles for delivery to the autophagosomeChandra S, Mannino PJ, Thaller DJ, Ader NR, King MC, Melia TJ, Lusk CP. Atg39 selectively captures inner nuclear membrane into lumenal vesicles for delivery to the autophagosome. Journal Of Cell Biology 2021, 220: e202103030. PMID: 34714326, PMCID: PMC8575018, DOI: 10.1083/jcb.202103030.
- TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis.Huang D, Xu B, Liu L, Wu L, Zhu Y, Ghanbarpour A, Wang Y, Chen FJ, Lyu J, Hu Y, Kang Y, Zhou W, Wang X, Ding W, Li X, Jiang Z, Chen J, Zhang X, Zhou H, Li JZ, Guo C, Zheng W, Zhang X, Li P, Melia T, Reinisch K, Chen XW. TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis. Cell Metabolism 2021, 33: 1655-1670.e8. PMID: 34015269, DOI: 10.1016/j.cmet.2021.05.006.
- A model for a partnership of lipid transfer proteins and scramblases in membrane expansion and organelle biogenesisGhanbarpour A, Valverde DP, Melia TJ, Reinisch KM. A model for a partnership of lipid transfer proteins and scramblases in membrane expansion and organelle biogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2101562118. PMID: 33850023, PMCID: PMC8072408, DOI: 10.1073/pnas.2101562118.
- ATG2 transports lipids to promote autophagosome biogenesisValverde DP, Yu S, Boggavarapu V, Kumar N, Lees JA, Walz T, Reinisch KM, Melia TJ. ATG2 transports lipids to promote autophagosome biogenesis. Journal Of Cell Biology 2019, 218: 1787-1798. PMID: 30952800, PMCID: PMC6548141, DOI: 10.1083/jcb.201811139.
- Maturation and Clearance of Autophagosomes in Neurons Depends on a Specific Cysteine Protease Isoform, ATG-4.2Hill 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. PMID: 30880001, PMCID: PMC6482087, DOI: 10.1016/j.devcel.2019.02.013.
- Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processesLystad 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. PMID: 30778222, PMCID: PMC7032593, DOI: 10.1038/s41556-019-0274-9.
- Delipidation of mammalian Atg8-family proteins by each of the four ATG4 proteasesKauffman 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. PMID: 29458288, PMCID: PMC6103404, DOI: 10.1080/15548627.2018.1437341.
- Erratum: Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3Nath S, Dancourt J, Shteyn V, Puente G, Fong W, Nag S, Bewersdorf J, Yamamoto A, Antonny B, Melia T. Erratum: Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. Nature Cell Biology 2014, 16: 821-821. DOI: 10.1038/ncb3017.
- Erratum: Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3Nath S, Dancourt J, Shteyn V, Puente G, Fong W, Nag S, Bewersdorf J, Yamamoto A, Antonny B, Melia T. Erratum: Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. Nature Cell Biology 2014, 16: 716-716. DOI: 10.1038/ncb3002.
- Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3Nath 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: 415-424. PMID: 24747438, PMCID: PMC4111135, DOI: 10.1038/ncb2940.
- The Lipidation Machinery Involved in Autophagosome Growth is Only Functional on Highly Curved MembranesNath S, Dancourt J, Puente G, Nag S, Yamamoto A, Antonny B, Melia T. The Lipidation Machinery Involved in Autophagosome Growth is Only Functional on Highly Curved Membranes. Biophysical Journal 2013, 104: 97a. DOI: 10.1016/j.bpj.2012.11.576.
- The Legionella Effector RavZ Inhibits Host Autophagy Through Irreversible Atg8 DeconjugationChoy A, Dancourt J, Mugo B, O’Connor T, Isberg RR, Melia TJ, Roy CR. The Legionella Effector RavZ Inhibits Host Autophagy Through Irreversible Atg8 Deconjugation. Science 2012, 338: 1072-1076. PMID: 23112293, PMCID: PMC3682818, DOI: 10.1126/science.1227026.
- SNARE Proteins Are Required for MacroautophagyNair 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. PMID: 21784249, PMCID: PMC3143362, DOI: 10.1016/j.cell.2011.06.022.
- Membrane Fusion in AutophagyTareste D, Yamamoto A, Melia T. Membrane Fusion in Autophagy. Biophysical Journal 2009, 96: 359a. DOI: 10.1016/j.bpj.2008.12.1811.
- Acetylation-Dependent Clearance of Soluble Mutant Huntingtin by AutophagyJeong 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.
- Selective Activation of Cognate SNAREpins by Sec1/Munc18 ProteinsShen J, Tareste DC, Paumet F, Rothman JE, Melia TJ. Selective Activation of Cognate SNAREpins by Sec1/Munc18 Proteins. Cell 2007, 128: 183-195. PMID: 17218264, DOI: 10.1016/j.cell.2006.12.016.
- Close Is Not EnoughMcNew J, Weber T, Parlati F, Johnston R, Melia T, Söllner T, Rothman J. Close Is Not Enough. Journal Of Cell Biology 2000, 150: 105-118. PMID: 10893260, PMCID: PMC2185554, DOI: 10.1083/jcb.150.1.105.