Division of Chaperones and Proteases

Molecular chaperones are central components of the cellular machinery that maintains protein homeostasis, and therefore have fundamental impact on cell physiology, aging and disease. Our goal is to understand the mechanisms of chaperone networks in protein biogenesis and quality control, and how these networks relate to cancer and neurodegeneration. We have three main research themes: (1) Biogenesis of proteins: A multi-layered machinery engages translating ribosomes to promote folding of newly synthesized proteins. We want to understand how this machinery guides nascent polypeptides to the native state, and how assembly of oligomeric protein complexes are achieved. (2) Cellular protein quality control: Perturbation of proteostasis activates quality control systems which refold and degrade misfolded proteins or sequester them into aggregates. We are investigating the organised aggregation of proteins in cells, and the mechanisms by which chaperones rescue aggregated proteins. (3) Propagation of protein misfolding from cell to cell: Various diseases such as neurodegeneration exhibit a complex pathology involving non-cell autonomous effects and progressive cell-to-cell spreading of protein misfolding. We want to understand how local protein misfolding is affecting neighboring cells and tissues and how proteostasis is orchestrated at the organismal level.

FUTURE OUTLOOK
We will continue to focus on the three main topics: (1) Biogenesis of proteins: What are the mechanisms of chaperone-assisted co-translational protein folding and assembly? To what extent are protein folding processes regulated by variations in translation speed? How do silent mutations related to cancer affect translation speed and protein folding? (2) Cellular protein quality control: How do Hsp70-based chaperone networks operate in protein disaggregation and refolding? What is the basis for the triage decision between degradation and refolding of misfolded proteins? (3) Propagation of protein misfolding from cell to cell: Which pathways and cellular factors mediate the spreading of protein aggregates from cell to cell? How does the chaperone network affect the formation and spreading of protein aggregates?