Cellular homeostasis, proliferation and stress responses
Cells need to cope with a multitude of stress conditions that relentlessly inflict damage to its most vital components. This includes insults to the DNA that threatens genome stability, damage of proteins that can then form toxic aggregates, or injury of whole organelles such as mitochondria and lysosomes that releases harmful components. Cells have developed sophisticated molecular responses to these stresses that maintain protein homeostasis and organelle function, and ensure genomic stability. We are interested in deciphering these responses and uncover how they counteract stress-induced cell death and aging-related degeneration, or maintain cell proliferation.
The ubiquitin-proteasome system (UPS) is critically involved in cellular stress responses. Ubiquitination triggers degradation of damaged proteins by the proteasome, or removal of protein aggregates or hole organelles in the lysosome through autophagy. In addition, it regulates signalling pathways such as the DNA damage response and coordinates them with cell cycle progression.
A focus of our research has been the AAA+-type ATPase VCP/p97, which has emerged as a pivotal element of the UPS. It governs a variety of processes such as ER-associated degradation, ribosomal quality control, DNA damage responses as well as autophagy. Mutations in VCP/p97 in humans cause degenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), while pharmacological inhibition of VCP/p97 is considered as a strategy in cancer therapy. We have been working to reveal the molecular function of VCP/p97 and to understand how it cooperates with a host of accessory factors to trigger diverse stress responses in different compartments.
Cellular stress responses, proteostasis, ubiquitin-proteasome system, autophagy, lysosomal membrane permeabilization, lysophagy, mitophagy, DNA damage response, double strand break repair, cell cycle regulation.
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