Elucidation of the molecular mechanisms of myocardial autophagy regulation and MAPK pathway inactivation by SPRED proteins

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Cardiac functionality is dependent on a balanced protein turnover. Accordingly, regulated protein decay is critical to maintain cardiac function. In this project, we will investigate if deficiency of SPRED2, an intracellular repressor of ERK-MAPK signaling markedly expressed in human heart, results in impaired autophagy, heart failure, and shortened lifespan. SPRED2-deficient mice show cardiomyocyte hypertrophy, cardiac fibrosis, impaired electrical excitability, and severe arrhythmias. Mechanistically, cardiomyocyte dysfunction results from ERK hyperactivation and dysregulated autophagy, observed as accumulation of vesicles, vacuolar structures, and degenerated mitochondria. The diminished autophagic flux in SPRED2-/- hearts was reflected by a reduced LC3-II/LC3-I ratio and by decreased Atg7, Atg4B and Atg16L expression. Furthermore, the autophagosomal adaptors p62 and NBR1 and lysosomal CathepsinD accumulated in SPRED2-/- hearts. However, the molecular mechanisms how SPRED2 regulates autophagy remain enigmatic. SPRED2 has no intrinsic enzymatic activity, which makes an alternative mechanism of regulation of autophagy necessary. In this grant proposal, we would like to investigate in detail the pathways necessary to clarify how SPRED2 regulates vesicle transport required for RTK signaling but also final RTK inactivation by autophagy in cardiac myocytes. Elucidation of these molecular processes in vivo and ex vivo will be relevant in many areas of medical research, as a variety of diseases are triggered by disorders of MAPK pathway inactivation (“Rasopahties”), of intracellular transport, and lack of fusion of lysosomes (“Lysosomal Storage Diseases”).