Hgs, short for Hepatocyte growth factor-regulated tyrosine kinase substrate, is a crucial component of the Endosomal sorting required for transport (ESCRT) pathway. This pathway mediates protein sorting for degradation, playing a vital role in maintaining protein homeostasis (proteostasis) [1].

Cardiomyocyte-specific Hgs gene knockout mice were generated to explore its function. These knockout mice developed a phenotype similar to human restrictive cardiomyopathy (RCM). Proteomic analysis revealed that Hgs deficiency impaired lysosomal homeostasis in cardiomyocytes. It disrupted cholesterol transport and lysosomal integrity, leading to lysosomal storage disorder (LSD) with abnormal autophagosome accumulation and protein aggregation. Treatment with doxycycline to suppress protein aggregation alleviated cardiac fibrosis and diastolic dysfunction in these knockout mice. This shows that Hgs deficiency contributes to LSD-associated RCM-like cardiomyopathy, uncovering a novel role of Hgs in regulating cardiac lysosomal homeostasis and proteostasis [1].

In conclusion, Hgs is essential for maintaining protein and lysosomal homeostasis, especially in the heart. The use of Hgs gene knockout mouse models has provided important insights into the role of Hgs in restrictive cardiomyopathy, highlighting its significance in understanding the molecular mechanisms underlying this disease [1].

References:

1. Li, Zhenhua, Wang, Tianle, Xin, Chong, Yang, Xiao, Wang, Jian. 2022. Hgs Deficiency Caused Restrictive Cardiomyopathy via Disrupting Proteostasis. In International journal of biological sciences, 18, 2018-2031. doi:10.7150/ijbs.69024. https://pubmed.ncbi.nlm.nih.gov/35342336/