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Signalling-Pathways Regulating the Dynamic Localization of Z-disc-Associated Proteins

Subject Area Cell Biology
Term from 2010 to 2018
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 148688621
 
Final Report Year 2019

Final Report Abstract

The Z-disc is a major structural part of the myofibril which has to withstand enormous mechanical strain. It is composed of a limited number of structural proteins but a plethora of polypeptides are associated with the Z-disc, at least transiently. This dynamic nature is important to allow for continuous replacement of damaged components and to keep up adaptability to varying physiological needs. The main aim of our project was to decipher how this dynamic behaviour of Z-disc components is regulated, and in particular, which signalling pathways influence protein interactions and protein turnover. Extensive biochemical studies allowed us to establish the most comprehensive map of proteinprotein interactions at the Z-disc known to date. To understand how these interactions are regulated, we established in close collaboration with P4 a map of protein phosphorylations elicited by contractile activity. This data provided a basis for detailed analyses of protein interaction dynamics, which we investigated at the sub-cellular level using BiFC and FRAP. We focused our investigations on the large actin-binding protein filamin C (FLNc) and its ligands and found that they are particularly dynamic Z-disc-associated proteins and that phosphorylation fine-tunes this dynamic behavior. The main function of these proteins seems to sense mechanically damaged areas in myofibrils and to initiate subsequent repair. In this context we found, in close collaboration with P10, that the homeostasis of FLNc is controlled by interactions with HSPB8, BAG3 (linking to chaperoneassisted selective autophagy and transcription regulation) and myopodin/Synpo2 (linking to vesicle formation and autophagy machinery). Mutations in the genes encoding various Z-disc proteins, in particular FLNc and its interaction partners, cause severe muscular diseases. We generated a knock-in mouse model mimicking the most prevalent human disease-causing FLNC mutation (p.W2710X) and found amplified lesion pathology as the major pathomechanism. In addition, we were also very successful in generating and analyzing mouse lines expressing BAG3-EGFP or the human pathogenic mutant BAG3P209L-EGFP in a muscle-specific and/or cardiac-specific manner. Cardiomyocytes expressing the pathogenic BAG3 mutant protein exhibit a phenotype mimicking the human pathology. These combined findings impressively illustrate the enormous importance of Z-disc protein-associated homeostasis mechanisms for muscle function and explain the dramatic impact of mutations affecting components of this machinery in protein aggregate myopathies.

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