Essential role for UVRAG in autophagy and maintenance of cardiac function

Abstract

AIMS: Ultraviolet irradiation resistance-associated gene (UVRAG) is a tumour suppressor candidate that regulates cell autophagy and endocytosis. However, the in vivo function of UVRAG remains poorly understood. We sought to determine the physiological role of UVRAG in the heart. METHODS AND RESULTS: We characterized mice with disruption of the UVRAG gene by piggyBac (PB) transposon insertion. PB construct was inserted into intron 14 of the UVRAG gene and disruption of UVRAG transcript was confirmed by reverse transcript-polymerase chain reaction. Immunoblotting revealed that UVRAG was deficient in multiple tissues. Autophagic flux was attenuated in UVRAG-deficient (UVRAG(PB/PB)) mouse embryonic fibroblasts. In UVRAG-deficient hearts, autophagosomes were accumulated and autophagic flux, assessed as the increased protein abundance of LC3 II in chloroquine-treated animals, was impaired. UVRAG-deficient mice were viable, fertile, and developmentally normal. However, they developed age-related cardiomyopathy associated with compromised cardiac function. In addition, inflammatory response was enhanced in UVRAG-deficient hearts. CONCLUSION: Collectively, our findings suggest that UVRAG is essential for the regulation of autophagy and maintenance of cardiac function.