The interplay between autophagy and the ubiquitin-proteasome system in cardiac proteotoxicity
1Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA.
Abstract:
Proteotoxicity refers to the detrimental effects of damaged/misfolded proteins on the cell. Cardiac muscle is particularly susceptible to proteotoxicity because sustained and severe proteotoxic stress leads to cell death and the cardiac muscle has very limited self-renewal capacity. The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) are two major pathways responsible for degradation of most cellular proteins. Alterations of UPS and ALP functions are associated with the accumulation of proteotoxic species in the heart, a key pathological feature of common forms of heart disease including idiopathic, ischemic, and pressure-overloaded cardiomyopathies and a large subset of congestive heart failure. Emerging evidence suggests that proteasome inhibition or impairment activates autophagy and conversely, acute ALP inhibition may sometimes increase intrinsic proteasome peptidase activities but chronic ALP inhibition hinders UPS performance in ubiquitinated protein degradation. The exact molecular basis on which the two degradative pathways interact remains largely undefined. Here we review current understanding of the roles of the UPS and autophagy in the control of cardiac proteotoxicity, with a specific focus on the crosstalk between the two pathways. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
Insights
Cardiac proteotoxicity, caused by protein damage, harms heart muscle. The ubiquitin-proteasome system (UPS) and autophagy pathways interact to manage this, crucial for heart disease treatment.
Area of Science:
- Cardiovascular Biology
- Cellular Proteostasis
- Molecular Medicine
Background:
- Proteotoxicity, the cellular damage from misfolded proteins, is detrimental to cardiac muscle due to its limited regenerative capacity.
- Impaired function of the ubiquitin-proteasome system (UPS) and autophagic-lysosomal pathway (ALP) contributes to proteotoxic species accumulation in heart disease.
- This accumulation is a hallmark of various cardiomyopathies and heart failure.
Purpose of the Study:
- To review the roles of the UPS and autophagy in controlling cardiac proteotoxicity.
- To highlight the critical crosstalk and interactions between these two major protein degradation pathways.
- To provide insights into the molecular mechanisms governing their interplay in the context of heart disease.
Main Methods:
- Literature review of current research on protein degradation pathways in the heart.
- Analysis of studies investigating the ubiquitin-proteasome system (UPS) and autophagy.
- Examination of evidence on the interaction and crosstalk between UPS and ALP in cardiac proteotoxicity.
Main Results:
- Both UPS and ALP are essential for degrading cellular proteins and preventing proteotoxicity in the heart.
- Dysregulation of UPS and ALP is implicated in the pathogenesis of common heart diseases.
- Evidence suggests complex crosstalk, where inhibition of one pathway can affect the other, though chronic inhibition of ALP impairs UPS function.
Conclusions:
- Understanding the interplay between UPS and autophagy is crucial for addressing cardiac proteotoxicity.
- Targeting these pathways and their crosstalk may offer novel therapeutic strategies for heart disease.
- Further research is needed to fully elucidate the molecular basis of UPS-autophagy interaction in cardiac proteostasis.
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