Proteasome malfunction activates macroautophagy in the heart

Protein quality control (PQC) senses and repairs misfolded/unfolded proteins and, if the repair fails, degrades the terminally misfolded polypeptides through an intricate collaboration between molecular chaperones and targeted proteolysis. Proteolysis of damaged proteins is performed primarily by the ubiquitin-proteasome system (UPS). Macroautophagy (commonly known as autophagy) may also play a role in PQC-associated proteolysis, especially when UPS function becomes inadequate. The development of a range of heart diseases, including bona fide cardiac proteinopathies and various forms of cardiac dysfunction has been linked to proteasome functional insufficiency (PFI). Both PFI and activation of autophagy have been observed in the heart of well-established mouse models of cardiac proteinopathy. A causal relationship between PFI and autophagic activation was suggested by a study using cultured cardiomyocytes but has not been established in the heart of intact animals. Taking advantage of an autophagy reporter, we demonstrated here that pharmacologically induced proteasome inhibition is sufficient to activate autophagy in cardiomyocytes in both intact animals and cell cultures, unveiling a potential cross-talk between the two major degradation pathways in cardiac PQC.