BBS Faculty Member - Tobias Walther

Tobias Walther

Department of Molecular Metabolism, HSPH
Department of Cell Biology, HMS

Harvard School of Public Health
665 Huntington Avenue
Building I, Room 207
Boston, MA 02115
Tel: 617-495-1000
Email: twalther@hsph.harvard.edu
Visit my lab page here.



Life is characterized by the assembly of complex structures that are maintained by a continuous flux of energy through these systems. At the molecular level, structure and energy processes intersect at lipids. Our laboratory determines the mechanisms how cells regulate the abundance of lipids, how they store lipids to buffer fluctuation in their availability and how these processes function in cell physiology.

Very little has been known about the mechanisms of cellular lipid storage, which occurs in Lipid Droplets (LDs). These organelles form an organic phase bounded by a monolayer of phospholipids into which specific proteins are embedded. We identified factors important for normal lipid droplets and our studies reveal the biochemical mechanisms leading to LD formation and recruitment of specific proteins to these organelles. We further discovered an elegant feed-back mechanism cells use to balance the need for surface phospholipids with the increase of core TG by targeting key enzymes to LDs in response to deficiency of phospholipids there. These fundamental discoveries of the last two years on LD biology likely are important for our understanding of lipid storage, membrane biology and metabolism. They will likely have important consequences for development of therapeutic approaches to treat metabolic diseases, such as obesity, metabolic syndrome and atherosclerosis. We have shown the relevance of our findings obtained in cells for model organisms, such as flies and mice. Recently, we extended our studies of lipid storage enzymes to humans.

Uniquely among lipids, sphingolipids are not stored, and as a consequence their abundance is regulated acutely by posttranslational mechanisms according to need. Sphingolipid are primarily found in the plasma membrane where they are important for membrane integrity and organization. Starting from unbiased screens, we identified cellular signaling pathways maintaining sphingolipid homeostasis. These processes are curial to maintain normal plasma membranes. We found that the organization of the plasma membrane into lateral domains of distinct protein and lipid composition is crucial for this regulation. We now determine how signaling cascades coordinate the different steps of sphingolipid synthesis and regulate cellular pathways, such as vesicular trafficking accordingly. Our future studies will reveal these mechanisms and show how these processes impact he many processes and pathologies, ranging from plasma membrane integrity to cancer development or neurodegenerative disease, where sphingolipids are crucial.



Last Update: 9/11/2020



Publications

Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme. Sui X, Wang K, Gluchowski NL, Elliott SD, Liao M, Walther TC, Farese RV Jr.Nature. 2020 May;581(7808):323-328. doi: 10.1038/s41586-020-2289-6. Epub 2020 May 13 PMID: 32433611

Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration. Petit CS, Lee JJ, Boland S, Swarup S, Christiano R, Lai ZW, Mejhert N, Elliott SD, McFall D, Haque S, Huang EJ, Bronson RT, Harper JW, Farese RV Jr, Walther TC.Proc Natl Acad Sci U S A. 2020 May 12;117(19):10565-10574. doi: 10.1073/pnas.1913956117. Epub 2020 Apr 28.PMID: 32345721
 
Partitioning of MLX-Family Transcription Factors to Lipid Droplets Regulates Metabolic Gene Expression.
Mejhert N, Kuruvilla L, Gabriel KR, Elliott SD, Guie MA, Wang H, Lai ZW, Lane EA, Christiano R, Danial NN, Farese RV Jr, Walther TC.Mol Cell. 2020 Mar 19;77(6):1251-1264.e9. doi: 10.1016/j.molcel.2020.01.014. Epub 2020 Feb 4 PMID: 32023484
 
LDAF1 and Seipin Form a Lipid Droplet Assembly Complex. Chung J, Wu X, Lambert TJ, Lai ZW, Walther TC, Farese RV Jr.Dev Cell. 2019 Dec 2;51(5):551-563.e7. doi: 10.1016/j.devcel.2019.10.006. Epub 2019 Nov 7.PMID: 31708432



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