DFG Collaborative Research Center 1177
Molecular and Functional Characterization of Selective Autophagy
Collaborative Research Centres (CRCs) are long-term university-based research institutions, established for up to 12 years, in which researchers work together within a multidisciplinary research programme.
The CRC 1177 is coordinated at Goethe University by Max-Planck-Fellow Prof. Dr. Ivan Đikić. The CRC strenghtens cooperation with institutions in the Rhine-Main-Area (the MPI of Biophysics, the Johannes Gutenberg University Mainz, and the Georg-Speyer-Haus, Institut für Tumorbiologie und experimentelle Therapie, and the Institut für Molekulare Biologie gGmbH) and beyond (Ludwig-Maximilians-Universität München, Eberhard Karls Universität Tübingen, and Albert-Ludwigs-Universität Freiburg).
Below you can find an overview on project parts of CRC 1177 we are envolved in:
Avidity-driven assembly and properties of cargo in selective autophagy
The properties, dimensions, and characteristics of autophagic cargo are highly diverse, ranging from organelles enclosed in membranes to protein assemblies lacking membranes. These cargoes vary in size, extending to the scale of microns, and can adopt a fixed or mobile arrangement. The impact of these cargo features on the process of autophagosome biogenesis remains unclear. Therefore, the main focus of this project is on elucidating how the physical properties of selective cargo affect their engulfment and subsequent degradation. To decipher the molecular factors governing the selective degradation of cargo, we will use a combination of cell biology, biochemistry, and structural methods, including ultrastructural characterization by correlative cryo-electron tomography.
Control of aberrant TDP-43 phase transitions by the selective autophagy machinery
Aberrant phase transitions may underlie the formation of TDP-43 (TAR DNA binding protein of 43 kDa) aggregates in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease. Autophagy is a route for clearance of TDP-43 aggregates, however it is unknown how the autophagy machinery recognizes and deals with different biophysical states of TDP-43, i.e. how soluble vs. liquid-like vs. solid-like TDP-43 condensates are degraded. In this project, we will combine in vitro, cellular and computational studies to uncover how the selective autophagy machinery recognizes and deals with different biophysical states of TDP-43 (soluble vs. liquid-like vs. solid-like condensates) and how aberrant TDP-43 condensates or other protein aggregates affect autophagic flux.
Quantitative proteomics and integrated systems biology
Building on its success from previous funding periods, this project includes a proteomics platform and a central data integration platform. Together, they will serve all CRC members with expertise in quantitative proteomics, give access to all CRC-generated retrospective datasets, link them to external repositories, and provide tools to search, analyze and interpret disparate datasets.
Completed Project Parts
Molecular principles of ER-phagy pathways
The endoplasmic reticulum (ER) is dynamically remodeled to adapt its structure to cellular needs. This process is mediated via selective autophagy (ER-phagy) involving reticulon-type receptors, namely FAM134B and RTN3. Here, we propose to analyze how the ER-phagy receptor FAM134B is regulated and how cargo selection is driven. In particular, we will investigate the interactome of FAM134B to identify potential regulators of ER-phagy. In addition, we aim to further study the role of ER chaperones Calnexin (CANX) and SIGMA-R1 that may act as FAM134B co-receptors for ER-phagy. Taken together, this study will help deciphering the role of ER-phagy in maintaining ER size, functionality, and turnover.