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Systematic exploration of peroxisomal structure and function

Periodic Reporting for period 4 - PeroxiSystem (Systematic exploration of peroxisomal structure and function)

Reporting period: 2020-03-01 to 2020-08-31

Peroxisomes are fascinating organelles that are found in almost all eukaryotes. Peroxisomes participate in central pathways of cellular metabolism such as β-oxidation of fatty acids, amino acid catabolism and detoxification of reactive oxygen species as well as in recently identified non-metabolic processes such as antiviral innate immunity. Peroxisomes have complex biogenesis and degradation possibilities, are actively distributed during cell division and possess their own targeting and translocation machineries. Additionally, peroxisomes are remarkably diverse in shape, size, number and content. This diversity depends on the cell type and environment, and can be rapidly regulated in response to diverse signals. Hence, peroxisomes represent a dynamic and complex system that has biological ‘inputs’ and whose biological processes could be modelled with enough information to predict ‘outputs’.

Additionally a large number of peroxisomal disorders with dramatic phenotypes have been described and malfunctions in peroxisomes contribute to the etiology of Alzheimer's and Parkinson's diseases, aging, cancer and type 2 diabetes.

We are using systems cell biology approaches in yeast in an attempt to understand peroxisomes as a complete biological system.

We are specifically interested in:

Identifying new functions of peroxisomes

Discovering new peroxisomal proteins

Identifying peroxisome contact sites with other organelles

Systematically characterizing the peroxisome proteome under different conditions

Further understanding how proteins are targeted to peroxisomes

Identifying the peroxisomal protein quality control machinery
The work supported by the ERC CoG "Peroxisystem" has resulted in 23 manuscripts demonstrating the breadth of discoveries made thanks to ERC support. Specifically since the begging of the grant period we were able to:

1. Discover many new peroxisomal proteins never before studied
2. Uncover a function for many new peroxisomal proteins
3. Demonstrate that there are subpopulations of peroxisomes in cells
4. Discover a new targeting pathway to peroxisomes (Pex9) and the rules governing substrate selectivity for this pathway
5. Create a whole organelle peroxisome protein-protein interaction map
6. Create mini peroxisome libraries with mutants in all peroxisomal proteins to enable rapid characterization of new peroxisomal proteins.
7. Create a new tool to study contact sites
8. Define the "gold standard" criteria for experimentally defining a contact site tether
9. Uncover all peroxisomal contact sites and name them
10. Find two new contact site tethers for the peroxisome-mitochondria contact
11. Describe the function of the peroxisome-mitochondria contact

In addition, we have made a unique tool for the entire yeast cell biology community that should revolutionize the exploration of gene functions (the SWAT approach). We also wrote several (4) reviews and an opinion piece intended to summarize the field and explore new hypotheses and ideas. We have also created a free online database for use by all researchers in the field of cell biology that should enable exploration of gene functions (dHITS).