Proteins are synthesized as nascent polypeptide chains by the ribosome and must fold into their correct three‑dimensional structures to carry out their specific biological functions within the cell. Their spatial conformation is carefully maintained throughout their functional lifetime, after which they are degraded in a timely and efficient manner.

Mammalian cells contain many thousands of diverse proteins that drive cellular activities, all of which must be precisely regulated. A balanced proteome—referred to as protein homeostasis or proteostasis—relies on the coordinated actions of molecular chaperones, proteolytic systems, protein degradation machineries, and their regulatory factors to ensure proper cellular function and survival.

Protein homeostasis can be disrupted by endogenous or external stresses, leading to the accumulation of misfolded proteins that are toxic to the cell. Understanding how molecular chaperones and other components of the proteostasis network operate is therefore of fundamental medical importance, as failures in protein homeostasis are associated with numerous diseases, including cancer and neurodegenerative disorders.

Research areas

ER chaperones

The endoplasmic reticulum (ER) is a major site for protein folding and maturation within the within the Eukaryotic cell. Proteins that reside within the ER along with proteins destined for the Golgi, plasma membrane, and extra cellular space are synthesized by ribosomes that are attached to the ER membrane. The newly translated polypeptide chain is acted upon by protein folding and post translational modification machinery that include molecular chaperones, glycosylating enzymes and oxidoreductases. The sole ER Hsp 70 chaperone, referred to as BiP, is an abundant protein that plays a major role in protein folding within this compartment. BiP action is influenced by its co-chaperones and other regulators (such as GRP170), which act to stimulate BiP activity - thereby driving protein folding.

The cooperation between chaperones and other post translational modifying enzymes ensure successful preservation of protein structure and therefore its function. We seek to understand - at the molecular level - how these processes regulate protein homeostasis, and how their aberrant function could affect cell fitness.

Unfolded protein response
The ER is the first compartment of the secretory pathway and is therefore critically important in specialized secretory cells, such as insulin‑producing β cells and antibody‑producing plasma cells. A sudden increase in the demand for secretory protein production places substantial pressure on the ER’s folding and maturation capacity, potentially leading to the accumulation of misfolded proteins. This condition, known as ER stress, is toxic to cells.
To restore homeostasis, cells activate a compensatory signaling pathway that enhances ER folding capacity to match the increased load. This pathway, termed the unfolded protein response (UPR), is mediated primarily by three transmembrane sensors: IRE1, PERK, and ATF6. These activator proteins span the ER membrane, with domains in both the ER lumen and the cytosol, enabling signal transmission between compartments. The UPR monitors misfolded proteins and coordinates both transcriptional responses in the nucleus and translational adjustments in the cytosol to rebalance ER function. Although the overall physiological framework of the UPR is well established, the precise molecular mechanisms governing signal detection and transmembrane propagation remain incompletely understood.