This project addresses the fundamental question of how cells identify and selectively remove individual damaged proteins.
Degradation of damaged proteins is essential for the survival of all cells. Impaired protein turnover can lead to diverse disorders such as neurodegeneration. In human cells, a system of quality control factors can surveil the proteome for damage. For example, misfolded proteins can be recognized and selectively degraded to prevent the build-up of toxic aggregates throughout life and in response to stress. In addition, proteins can experience any of several hundred chemical modifications throughout their life-cycle. How cells monitor the proteome for these types of modifications and potential signs of damage remains poorly understood.
In this project, we aimed to identify chemical modifications that can act as marks of protein damage, to induce their selective removal. More specifically, we asked: How can we measure the impact of individual protein modifications on protein turnover? Which known forms of chemical damage could serve as triggers of selective protein degradation in human cells? What is the underlying cellular machinery and how can it recognize chemically damaged proteins at the molecular level? And lastly, how does this chemical protein surveillance contribute to maintaining an intact proteome under physiological conditions and proteotoxic stress.
This project was designed to test the long-standing hypothesis that chemical protein modifications could provide a generic signal, that allows human cells to broadly survey the proteome for damage. In addition to its contribution to our fundamental understanding of cell homeostasis, these questions are central to understanding the mechanisms at play when protein homeostasis is perturbed, for example during ageing or neurodegeneration. In addition, the machinery that mediates selective protein degradation can be reprogrammed to target other proteins in a cell by pharmacological means. For example, the class of IMiD drugs mimics a chemical modification recognized by the ubiquitin ligase CUL4/CRBN and redirects its activity towards therapeutically relevant proteins, such as IKZF1. This mechanism underlies the action of the drug thalidomide, which has been highly successful in the treatment of multiple myeloma. Identifying other such chemical protein surveillance factors could therefore also open up avenues for designing new targeted protein therapeutics in future projects.
