Chapter 13 - Defense Against Proteotoxic Stress in the Heart: Role of p62, Autophagy, and Ubiquitin–Proteasome System

Abstract

Protein quality control (PQC) maintains protein hemostasis and is critical to cell survival and function. PQC defends against proteotoxic stress by concerted actions of chaperone and protein degradation machineries. Misfolded proteins may first be salvaged by chaperon-mediated folding and refolding, and when failed, are marked for degradation by the ubiquitin proteasome system (UPS), chaperon-mediated autophagy (CMA), or (macro)autophagy. PQC can be overwhelmed by proteotoxic stress, leading to the development of various human diseases, including cardiac diseases. Desmin-related cardiomyopathy, an autosomal inherited disease, is characterized by cardiac protein aggregation and proteasome functional insufficiency (PFI), indicative of PQC insufficiency. Enhancement of proteasome function and attenuation of protein aggregation both alleviate the development of DRC, demonstrating that inadequate PQC plays a major pathogenic role in desmin-related cardiomyopathy (DRC). Furthermore, autophagy is compensatorily activated in DRC mouse hearts and protects cardiomyocytes from proteotoxic stress. The ubiquitin receptor p62 is also upregulated in DRC mouse hearts, and may play important roles in antagonizing proteotoxic stress by promoting the sequestration of misfolded proteins and selective autophagy via its multifunctional domains. Finally, cardiac proteinopathy due to insufficient PQC may be extrapolated to other common forms of cardiac diseases, and enhancing proteasome function benefits the heart from ischemia/reperfusion injury, suggesting that PQC improvement should be explored as a novel therapeutic avenue to prevent and treat a large subset of heart diseases.