Hgs Deficiency Caused Restrictive Cardiomyopathy via Disrupting Proteostasis

The molecular mechanisms underlying restrictive cardiomyopathy (RCM) are not fully understood. Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) is a vital element of Endosomal sorting required for transport (ESCRT), which mediates protein sorting for degradation and is crucial for protein homeostasis (proteostasis) maintenance. However, the physiological function and underlying mechanisms of HGS in RCM are unexplored. We hypothesized that HGS may play vital roles in cardiac homeostasis. Cardiomyocyte-specific Hgs gene knockout mice were generated and developed a phenotype similar to human RCM. Proteomic analysis revealed that Hgs deficiency impaired lysosomal homeostasis in cardiomyocytes. Loss of Hgs disrupted cholesterol transport and lysosomal integrity, resulting in lysosomal storage disorder (LSD) with aberrant autophagosome accumulation and protein aggregation. Suppression of protein aggregation by doxycycline treatment attenuated cardiac fibrosis, and diastolic dysfunction in Hgs-knockout mice. These findings uncovered a novel physiological role of HGS in regulating cardiac lysosomal homeostasis and proteostasis, suggesting that the deficient HGS contributes to LSD-associated RCM-like cardiomyopathy.