The plasma membrane is the defining feature of cells and serves as their interface with the external environment. Current models posit that it is laterally organized in domains of distinct protein and lipid composition that are important for the efficient orchestration of key reactions of transport and communication, for example involved in endocytosis. However, despite tremendous advances in the comprehension of membrane processes and structure, physiological functions of plasma membrane organization are not yet clear. To overcome limitations of complex models used for investigation, we will focus on studying plasma membrane organization in yeast. This model system has prominent protein and lipid segregation in the plasma membrane and is amenable to molecular, biochemical, genetic and systems approaches. In this project, we will capitalize on our discovery of eisosomes, large protein complexes underlying the plasma membrane, as principal organizers plasma membrane domains in yeast.
We aim to define the molecular mechanisms and cellular functions of plasma membrane organization. We hypothesize that eisosomes assemble into a stable membrane scaffold that plays fundamental roles in phosphoinositide cell biology and endocytosis. To test this model, we will use directed biochemical, structural biology, cell biology experiments combined with unbiased analytical tools, including state-of-the-art proteomics and systematic genetics. By tackling these central questions on plasma membrane biology and elucidating the function of membrane organization by eisosomes, we will address a fundamental cell biology problem. Salient features of biological systems, including the structure of eisosome proteins are most often evolutionary conserved. Our findings will therefore likely have a broad impact on membrane research. They might also have therapeutic implications for a wide range of human pathologies where plasma membrane organization is implicated.
In the proposed project, we will determine the mechanism and physiological functions of plasma membrane organization by eisosomes, especially in phosphoinositides metabolism and endocytosis. By addressing these questions, we will reveal fundamental principles of plasma membrane biology with broad implications.
| Olson, D K; Fröhlich, F; Farese Jr, R V et al. (2016) Taming the sphinx: Mechanisms of cellular sphingolipid homeostasis. Biochim Biophys Acta 1861:784-792 |
| Baskin, Jeremy M; Wu, Xudong; Christiano, Romain et al. (2016) The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. Nat Cell Biol 18:132-8 |
| Fröhlich, Florian; Olson, Daniel K; Christiano, Romain et al. (2016) Proteomic and phosphoproteomic analyses of yeast reveal the global cellular response to sphingolipid depletion. Proteomics 16:2759-2763 |
| Kory, Nora; Thiam, Abdou-Rachid; Farese Jr, Robert V et al. (2015) Protein Crowding Is a Determinant of Lipid Droplet Protein Composition. Dev Cell 34:351-63 |
| Fröhlich, Florian; Petit, Constance; Kory, Nora et al. (2015) The GARP complex is required for cellular sphingolipid homeostasis. Elife 4: |
| Shibuya, Aya; Margulis, Neil; Christiano, Romain et al. (2015) The Erv41-Erv46 complex serves as a retrograde receptor to retrieve escaped ER proteins. J Cell Biol 208:197-209 |
| Olson, Daniel K; Fröhlich, Florian; Christiano, Romain et al. (2015) Rom2-dependent phosphorylation of Elo2 controls the abundance of very long-chain fatty acids. J Biol Chem 290:4238-47 |
| Bazzini, Ariel A; Johnstone, Timothy G; Christiano, Romain et al. (2014) Identification of small ORFs in vertebrates using ribosome footprinting and evolutionary conservation. EMBO J 33:981-93 |
| Harrison, Megan S; Hung, Chia-Sui; Liu, Ting-ting et al. (2014) A mechanism for retromer endosomal coat complex assembly with cargo. Proc Natl Acad Sci U S A 111:267-72 |
| Christiano, Romain; Nagaraj, Nagarjuna; Fröhlich, Florian et al. (2014) Global proteome turnover analyses of the Yeasts S. cerevisiae and S. pombe. Cell Rep 9:1959-1965 |
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