A hallmark of eukaryotic cells is the ability to compartmentalize essential reactions into membrane-bound and membrane-free organelles. Membrane-bound organelles work together in networks through transport vesicles and inter-organelle contact sites. Membrane-free organelles, such as mRNA-protein (RNP) granules, exist in a separate density phase from the surrounding cytosol and play critical roles throughout the mRNA life cycle.

Recent efforts have begun to define cells through transcriptome and proteome analyses, however little is known about how these materials come together to control cellular architecture and organization. Our recent work together with others suggest that the endoplasmic reticulum (ER) plays a critical role in organizing cellular materials through the formation of a new class of contact sites with membrane-free organelles linked to transcriptome homeostasis (Lee et al. Science 2020).

Our lab focuses on understanding how, why, and when membrane-bound and membrane-free organelles form contact domains to control the mRNA life cycle and cellular function in health and in disease.

Membrane-free organelle dynamics

Contrary to the importance of mitochondrial and endosome fission on metabolism and cargo trafficking, respectively, the significance of membrane-free organelle fission is a mystery and remains unexplored. One focus of our lab is investigating how and why membrane-free organelles, such as RNP granules, undergo fission. These studies will build off of initial discoveries showing that ER tubules localize to the sites of P-body and stress granule fission (Lee et al. 2020).

ER tubules (in red) localize to the sites of P-body (in green) fission.

ER morphology, RNP granule abundance, and mRNA life cycle

Shape follows function when discussing many membrane-bound organelles and the ER is a prime example. Pancake-shaped cisternal ER domains function primarily as sites of mRNA translation and nascent protein translocation. Tubular ER domains are sites of interaction with other organelles, lipid transfer, and calcium uptake and release. A second focus of our lab is elucidating how the relationship between ER shape and RNP granules affects mRNA bioavailability. These studies will delve deeper into the observation that P-body (mRNA silencing) abundance increases when there are more ER tubules, and decreases when there is ribosomal-studded cisternal ER (Lee et al. 2020).

New tools to resolve and evaluate inter-organelle contact

The cytoplasm of the cell is a crowded environment packed with macromolecules, the cytoskeleton, membrane-bound and membrane-free organelles. A third focus of our lab is developing new approaches and tools to resolve transient interactions between organelles within the crowded cytoplasm. For example, we designed an ER-P-body contact sensor that is capable of resolving ER-P-body contact during the dynamic fission process of P-bodies (Lee et al. 2020).

ER-P-body contact (in red) during the dynamic fission process of P-bodies (in green).

We are always looking for motivated, creative, positive minds to join us. If this research sounds interesting to you, then we encourage you to learn more about joining us!