Assistant Professor, BCMB
Organelle Biogenesis and Function
Intracellular membrane-bound organelles are a hallmark of all eukaryotic cells. Understanding how cells generate different organelles that display characteristic morphologies remains one of the central problems in cell biology. Some organelles, like the endoplasmic reticulum (ER) and mitochondria are self-generating whereas other organelles such as peroxisomes and lipid droplets (LDs) can be generated de novo from specialized subdomains in the ER membrane. Remarkably little is known about the ER subdomains and how they regulate organelle biogenesis. Our lab utilizes multidisciplinary approaches to investigate formation and function of organelles at the ER subdomains in normal and pathological conditions.
The ER is a continuous membrane-bound organelle that extends from outer nuclear membrane to highly dynamic interconnected web of tubules in the cell periphery. The evolutionary conserved ER membrane proteins such as reticulons generate ER tubules. Reticulons and reticulon-like proteins harbor reticulon homology domain (RHD) that is proposed to bend the membrane to generate tubules. We previously discovered novel RHD containing ER shaping proteins, Pex30 and Pex30-like proteins in yeasts and multiple C2 domain containing transmembrane proteins (MCTP) in higher eukaryotes. Similar to reticulons, Pex30/MCTP generates tubules in vitro and in cells. However, unlike the reticulons, Pex30/MCTP are low abundance proteins and are enriched at specialized ER subdomains that are sites of nascent peroxisome and LD biogenesis. Using S. cerevisiae and mammalian cells, we are currently investigating molecular mechanisms of organelle formation and function with major focus on
- Determining the role of MCTP proteins in organelle biogenesis at ER subdomains.
- Investigating molecular mechanisms of nascent peroxisome vesicle formation from the ER membrane.
- Identifying novel regulators of peroxisome and LD biogenesis using genome-wide approaches.
Understanding the biogenesis of peroxisomes and LDs is not only a fundamental cell biological problem but also has important medical implications. Several life-threatening diseases are directly associated with the function of these organelles, including neurogenerative disorder like Zellweger syndrome associated with peroxisome function, and lipodystrophies, diabetes and obesity with LD function. For more details please visit our website.
Joshi AS* and Cohen S*. Lipid Droplet and peroxisome biogenesis: do they go hand in hand? Frontiers in Cell and Developmental Biology. 2019. May 31; 7:92.
Joshi AS*, Nebenfuehr B, Choudhary V, Satpute-Krishnan P, Levine TP, Golden A and Prinz WA*. Lipid droplet and peroxisome biogenesis occur at the same ER subdomains. Nature Communications. 2018 Jul 27;9(1):2940. *Co-corresponding authors.
Choudhary V, Golani G, Joshi AS, Cottier S, Schneiter R, Prinz WA and Kozlov MM. Architecture of Lipid Droplets in Endoplasmic Reticulum is determined by Phospholipid Intrinsic Curvature. Current Biology. 2018 March 19; 28(6): 915-926.
Huang X, Hu X, Zhou X, Joshi AS, Guo X, Zhu Y, Chen Q, Prinz WA, and Hu J. Sequences flanking the transmembrane segments facilitate mitochondrial localization and membrane fusion by mitofusin. Proceedings of the National Academy of Sciences. 2017 November 14; 114(46): E9863-E9872.
Joshi AS, Zhang H, and Prinz WA. Organelle biogenesis in the endoplasmic reticulum. Nature Cell Biology. 2017 Aug; 19(8): 876-882.
Joshi AS, Huang X, Choudhary V, Levine TP, Hu J, and Prinz WA. A family of membrane-shaping proteins at ER subdomains regulates pre-peroxisomal vesicle biogenesis. Journal of Cell Biology. 2016 Nov 21; 215(4): 515-529.