| Project Detail |
Cell control mechanism: the role of autophagy receptors
Autophagy or self-eating is a homeostatic process that degrades and removes unnecessary components from cells. However, when it comes to macromolecular complexes that involve the association of multiple macromolecules, such as proteins and RNA, the exact mechanism by which such dysfunctional assemblies are sensed by the cell remains elusive. The working hypothesis of the IntrinsicReceptors project, funded by the European Research Council, is that intrinsic receptors are implicated in the autophagy of macromolecular complexes. Researchers aim to identify candidate receptors and study how they are regulated. Given that many age-related diseases, such as Alzheimer’s disease, are characterised by aberrant accumulation of dysfunctional complexes, project results will pave the way for the design of novel interventions.
Macromolecular complexes (MC) are cellular machines that perform a wide array of vital tasks. They operate in a controlled, coordinated fashion within the crowded environment of the cell. Accumulation of dysfunctional MCs leads to age-related diseases. Despite recent technological advancements, it still remains elusive for many of them how excess or dysfunctional MCs are sensed and removed. I have recently established a role of intrinsic receptors in degradation of the nuclear pore complex and the clathrin-mediated endocytosis machinery by selective autophagy. Intrinsic receptors represent functional subunits of the macromolecular machine but can if needed recruit the autophagy machinery to engulf and degrade the complex. As such intrinsic receptors provide an in-built quality control function that monitors the assembly state and/or functionality of macromolecular machines. I hypothesize that this is a conserved and widely used principle existing within various MCs and that there is a common, yet unexplored, regulatory pathway underlying the intrinsic receptors’ mode of action. In the proposed project, I will employ a combination of genetic screening, mass spectrometry and cryo-electron tomography to systematically define intrinsic receptors and their working principles in cells. I will use systematic discovery approaches to determine how many MCs contain intrinsic receptors, how the degradation of intrinsic receptors and their cargo is regulated, and how this is orchestrated with autophagosome biogenesis. My results will not only provide insights into a novel cellular quality-control mechanism but also unravel novel aspects of selective autophagosome biogenesis. Importantly, both accumulation of dysfunctional complexes and impairment of autophagy are linked to aging and age-related diseases. Therefore, my results will contribute to understand the role of autophagy in these processes and have the potential to provide new pharmacological therapeutic avenues. |
