Thomas Melia, PhD
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Cell Biology
PO Box 208002, 333 Cedar Street
New Haven, CT 06520-8002
United States
About
Titles
Professor of Cell Biology
Appointments
Cell Biology
ProfessorPrimary
Other Departments & Organizations
Education & Training
- PhD
- Baylor College of Medicine (1999)
- BS
- Carnegie Mellon Univ (1992)
Research
Overview
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.
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
C. Patrick Lusk, PhD
Shanta Nag
Chenxiang Lin, PhD
Chunxiang Wu
Craig Roy, PhD
Kallol Gupta, PhD
Publications
2024
Spartin-mediated lipid transfer facilitates lipid droplet turnover
Wan N, Hong Z, Parson M, Korfhage J, Burke J, Melia T, Reinisch K. Spartin-mediated lipid transfer facilitates lipid droplet turnover. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2314093121. PMID: 38190532, PMCID: PMC10801920, DOI: 10.1073/pnas.2314093121.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords
2023
Growing thin — How bulk lipid transport drives expansion of the autophagosome membrane but not of its lumen
Melia T. Growing thin — How bulk lipid transport drives expansion of the autophagosome membrane but not of its lumen. Current Opinion In Cell Biology 2023, 83: 102190. PMID: 37385155, PMCID: PMC10528516, DOI: 10.1016/j.ceb.2023.102190.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsLC3B is lipidated to large lipid droplets during prolonged starvation for noncanonical autophagy
Omrane 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, 58: 1266-1281.e7. PMID: 37315562, PMCID: PMC10686041, DOI: 10.1016/j.devcel.2023.05.009.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsProtein 1 light chain 3BLarge lipid dropletsLight chain 3BStarvation triggersLipidation reactionNoncanonical autophagyLysosomal pathwayAutophagic processStore lipidsAutophagy mechanismLipid dropletsATG3Large LDsProlonged starvationHuman liver cellsLC3BTimes of scarcityStarvationLiver cellsMacrolipophagyAutophagicClose proximityAutophagyATG5MicrotubulesATG9 vesicles comprise the seed membrane of mammalian autophagosomes
Olivas 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.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsAtg9 vesiclesMammalian autophagosomesStyrene maleic acid lipid particlesLipid scramblase activityLC3-IIAutophagosomes formAutophagosome membraneMature autophagosomesScramblase activityAutophagosome formationAtg9Lipid transportMembrane growthAutophagosomesNanoscale organizationProtein-mediated transferProteinMembrane surface areaOrganellesVesiclesSeed membraneMembraneLipid particlesLipidsDifferent stages
2022
Functionalized DNA-Origami-Protein Nanopores Generate Large Transmembrane Channels with Programmable Size-Selectivity
Shen 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.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsExchange of macromoleculesCholesterol-rich membranesHybrid nanoporesSynthetic biologyBiophysical toolsSynthetic cellsTransmembrane channelsTransmembrane nanoporesDNA ringsProtein nanoporeCell membraneBacterial toxinsDNA origami techniqueLipid membranesAnalytical chemistryMacromolecule sizeDNA origamiMembraneProgrammable sizeNanoporesSized poresNucleoporinsAverage inner diameterCellsPneumolysinClosing the autophagosome is easy‐PC
Fuller D, Melia T. Closing the autophagosome is easy‐PC. The EMBO Journal 2022, 42: e113046. PMID: 36478568, PMCID: PMC9841321, DOI: 10.15252/embj.2022113046.Peer-Reviewed Original ResearchAltmetricMeSH Keywords
2021
Atg39 selectively captures inner nuclear membrane into lumenal vesicles for delivery to the autophagosome
Chandra 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.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAutophagosomesAutophagyAutophagy-Related ProteinsCytoplasmic VesiclesGreen Fluorescent ProteinsNuclear EnvelopeProtein DomainsReceptors, Cytoplasmic and NuclearSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsStructure-Activity RelationshipTime FactorsVacuolesVesicular Transport ProteinsConceptsInner nuclear membraneNuclear envelope lumenOuter nuclear membraneNuclear membraneSplit-GFP reporterNuclear envelope localizationINM proteinsAutophagy apparatusEnvelope localizationLumenal vesiclesLumenal domainCargo adaptorsAtg39Sequence elementsCorrelative lightVesiclesAutophagosomesMembraneNucleophagyAdaptorReporterProteinOverexpressionMotifTMEM41B 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.Peer-Reviewed Original ResearchCitationsAltmetricA model for a partnership of lipid transfer proteins and scramblases in membrane expansion and organelle biogenesis
Ghanbarpour 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.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsLipid transfer proteinEndoplasmic reticulumAutophagy protein ATG2Membrane dynamics processesTransfer proteinOrganelle biogenesisAutophagosome biogenesisCytosolic leafletOrganelle membranesMembrane expansionScramblasesVMP1Lipid homeostasisTMEM41BAtg9BiogenesisBulk lipidsProteinLipidsAtg2GolgiOrganellesReticulumLeafletsHomeostasis
2019
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. Journal Of Cell Biology 2019, 218: 1787-1798. PMID: 30952800, PMCID: PMC6548141, DOI: 10.1083/jcb.201811139.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsProtein-mediated lipid transferLipid transferLipid transfer proteinTransfers lipidsAutophagosome biogenesisAutophagosome membraneDonor membranesN-terminal fragmentDifferent organellesAutophagy proteinsAutophagosome formationKO cellsContact sitesSpecific machineryLipid homeostasisClear functionAtg2BiogenesisProteinDelivery of lipidsLipidsATG2AMembraneOrganellesAutophagosomes
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Cell Biology
PO Box 208002, 333 Cedar Street
New Haven, CT 06520-8002
United States