Membrane Dynamics and Intracellular Trafficking
Eukaryotic cells are characterized by their internal membrane compartments (organelles), which allow different cellular processes, such a protein folding or degradation, to take place in a well-adapted environment. However, in order for the cell to function as a whole, efficient communication must exist between the various organelles, including the endoplasmic reticulum (ER), Golgi apparatus and lipid droplets (LDs), as well as the plasma membrane. Proteins are transported from one compartment to another, and to the exterior of the cell, largely through vesicular trafficking. Lipids can be transported by both vesicular and non-vesicular routes, the latter often occurring at sites of close contact between organelles (membrane contact sites, MCS). Disruption of lipid trafficking and metabolism leads to human pathologies such as obesity, diabetes, cancer and neurodegenerative diseases. Lipid and vesicular trafficking pathways are also subverted for the propagation of numerous viruses, including Hepatitis C and enteroviruses.
Vesicles are formed by deformation of the membrane by coat complexes, a process regulated by small G proteins such as Arf1. Our group has been studying the Arf1 activator GBF1 and its role in the early secretory pathway. We have also discovered that GBF1 and its downstream effectors regulate lipid droplet metabolism and targeting of proteins to the surface of this organelle (Figure 1A). Lipid droplets are the major energy storage depots in cells, and play a central role in lipid trafficking and metabolism.
Each organelle has a unique membrane lipid composition, appropriate for its specific functions. For example, the endoplasmic reticulum membrane is made up of lipids conferring flexibility, thus facilitating protein translocation across it. The plasma membrane, in contrast, has high levels of cholesterol and saturated phospholipids that make it an excellent barrier to protect the cell from the external environment. Proteins also exploit the unique lipid compositions of organelle membranes in order to identify the compartment they need to associate with. We are studying targeting of proteins with amphipathic helices to organelles through direct protein-lipid interactions (Figure 1). We are also studying how organelle lipid compositions are maintained through lipid trafficking at membrane contact sites (Figure 2).
We are using a multidisciplinary approach consisting of advanced imaging (light and electron microscopy), biophysical, and in silico approaches, to explore the following research questions:
- Identification and characterization of components of membrane contact sites (MCS)
- coordination of vesicular trafficking and lipid transfer at MCS to maintain the unique lipid composition of intracellular organelles
- targeting of peripheral proteins to lipid droplets and bilayer-bounded organelles
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Walch L, Pellier E, Leng W, Lakisic G, Gautreau A, Contremoulins V, Verbavatz M#, Jackson CL#. (2018) GBF1 and Arf1 interact with Miro and regulate mitochondrial positioning within cells. Scientific Reports 8(1):17121. doi: 10.1038/s41598-018-35190-0. #co-corresponding authors
Copic A, Antoine-Bally S, Giménez-Andrés M, La Torre Garay C, Antonny B, Manni MM, Pagnotta S, Guihot J, Jackson CL. (2018) A giant amphipathic helix from a perilipin that is adapted for coating lipid droplets. Nat Commun. 9:1332. doi: 10.1038/s41467-018-03717-8.
Laband K, Le Borgne R, Edwards F, Stefanutti M, Canman JC, Verbavatz JM, Dumont J. (2017) Chromosome segregation occurs by microtubule pushing in oocytes. Nat Commun. 8:1499. doi: 10.1038/s41467-017-01539-8.
Jackson CL, Walch L, Verbavatz JM. (2016) Lipids and Their Trafficking: An Integral Part of Cellular Organization. Developmental Cell. 39(2):139-153 Review. doi: 10.1016/j.devcel.2016.09.030.
Petkovic M, Jemaiel A, Daste A, Specht CG, Izeddin I, Vorkel D, Verbavatz JM, Darzacq X, Triller A, Pfenninger KH, Tareste D,Jackson CL#,Galli T#. (2014) The SNARE Sec22b has a non-fusogenic function in plasma membrane expansion. Nature Cell Biology 16, 434–444. doi: 10.1038/ncb2937. #co-corresponding authors