Jon Audhya

Membrane trafficking program: vesicle transport and organelle dynamics during development and disease

The Audhya laboratory is committed to understanding the fundamental mechanisms by which membrane proteins, lipids, and other macromolecules are transported throughout eukaryotic cells. Our efforts are focused on two specific areas: COPII-dependent trafficking in the early secretory pathway, which enables movement of cargoes from the endoplasmic reticulum (ER) to ER-Golgi intermediate compartments (ERGIC), and endosomal sorting complex required for transport (ESCRT)-mediated biogenesis of multivesicular endosomes (MVEs), which function in the turnover of numerous ubiquitin-modified, membrane associated proteins and the secretion of exosomes. Alterations in these pathways can lead to disease, including neurodegeneration, cancer, diabetes, and immune dysfunction. In both cases, the core machineries that mediate cargo sorting and membrane remodeling have been largely identified, but the regulatory systems that are essential to appropriately control these processes remain poorly understood. We use a multidisciplinary approach to address this major gap in our knowledge, leveraging quantitative membrane biophysics to define mechanisms underlying membrane bending and the stabilization of membrane curvature, as well as biochemical methods to functionally reconstitute the action of proteins in vitro. Together with animal models (C. elegans and rodents) to analyze the impact of mutations in physiologically relevant settings and genome-edited human cell lines, including induced pluripotent stem cells (iPSCs), to define the subcellular dynamics of protein trafficking in the secretory and endocytic pathways, we are ideally positioned to understand how the COPII and ESCRT machineries function to maintain cellular homeostasis.

Imaging across scales. The Audhya lab uses multiple imaging techniques to understanding how vesicular transport and organelle dynamics are properly regulated, including super resolution light microscopy, electron microscopy/tomography, and single particle cryoEM.

Lab website

Faculty Director of the Optical Imaging Core

Representative publications:

Quinney, K., Frankel, E.B., Shankar, R., Kasberg, W., Luong, P., and Audhya, A. (2019) Growth factor stimulation promotes multivesicular endosome biogenesis by prolonging recruitment of the late-acting ESCRT machinery. Proc. Natl. Acad. Sci. USA. 116: 6858-6867.

Slosarek, E.L.#, Schuh, A.L.#, Pustova, I.#, Johnson, A., Bird, J., Johnson, M., Frankel, E.B., Bhattacharya, N., Hanna, M.G., Burke, J.E., Ruhl, D.A., Quinney, K., Block, S., Peotter, J.L., Chapman, E.R., Sheets, M.D., Butcher, S.E., Stagg, S.M., and Audhya, A. (2018) Pathogenic TFG mutations underlying hereditary spastic paraplegia impair secretory protein trafficking and axon fasciculation. Cell Rep. 24: 2248-2260. (# denotes equal contribution)

Frankel, E.B., Shankar, R., Moresco, J.J., Yates, J.R., Volkmann, N., and Audhya, A. (2017) Ist1 regulates ESCRT-III assembly and function during multivesicular endosome biogenesis in Caenorhabditis elegans embryos. Nat. Commun. 8: 1439.

Hanna, M.G., Block, S., Frankel, E.B., Hou, F., Johnson, A., Yuan, L., Knight, G., Moresco, J.J., Yates, J.R., Ashton, R., Schekman, R., Tong, Y., and Audhya, A. (2017) TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER-Golgi intermediate compartments. Proc. Natl. Acad. Sci. USA. 114: E7707-E7716.