Daniel Kaganovich
Partner Daniel Kaganovich studies how cells manage the folding structure and functional integrity of their proteome, adapting to rapidly changing conditions and responding to challenges and stress. We investigate protein structure, function, localization, and dynamics at the nano-scale to uncover the mechanism governing stress response, and its adaptability to external stimuli. Cells have the ability to tailor their protein folding stress response to suit their immediate needs, and respond differently to prolonged stress, acute stress, nutrient deprivation, and conditions of plenty. This adaptability may be the key to understanding the etiology of proteinopathies, such as neurodegenerative diseases, which are characterized by an acute failure of stress response in a particular place and time (in neurons and upon aging). Our work suggests that the adaptability of stress response is built into the very structure of the cell. We have identified several sub-organellar nano-structures, called junq, ipod, and stress foci, which are membraneless dynamic functional protein macro-assemblies that mediate the spatial and functional partitioning of protein folding and aggregation quality control in eukaryotes.
Example of a 3D timelapse (4D imaging) of an aggregate inclusion formation in mammalian cells. The nucleus in a CHO cell is marked with a far red fluorophore, Vimentin is tagged with mOrange2, and VHL, a misfolded protein, is tagged with a GFP tag. A z-stack was taken every 15 minutes for 25 hours (not all frames are shown).