The interplay between autophagy and the ubiquitin–proteasome system in cardiac proteotoxicity

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 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 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.

Role of the ubiquitin-proteasome system and autophagy in regulation of insulin sensitivity in serum-starved 3T3-L1 adipocytes

“…In contrast, knockdown of key genes essential for autophagy such as Atg7 has no effect on neuronal proteasomal activity in vitro and in vivo [38,39], but polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies [39], suggesting autophagy inhibition impaired the UPS function [38]. The accumulated ubiquitin-binding proteins such as p62 may be the culprit for this effect [3,34,38]. Our study found that pharmacological and genetic inhibition of autophagy in 3T3-L1 adipocytes reduced proteasome activity and promoted expressions of GFPu and total protein ubiquitination (Fig.…”

“…1A) and increased chymotrypsin-like proteasome activity (Fig. 1B) indicate that the UPS was activated by serum star- actions between these two degradation systems [3]. Traditionally, autophagy breaks down the unnecessary or dysfunctional cellular components through lysosomal degradation process.…”

“…Currently, a growing body of evidence suggests that autophagy also participates in the clearance of intracellular contents such as aggregated or misfolded proteins that were previously thought to be targeted exclusively by the UPS [30,31]. The UPS impairment or inhibition will result in accumulation of misfolded and aggregated protein leading to compensative activation of autophagy [3,32,33]. In agreement with this view, our study showed that UPS inhibition by BZM resulted in a compensative activation of autophagy, as characterized by significantly increased LC3-II expression and GFP-LC3 puncta formation (Fig.…”

Nuclear factor erythroid-2 related factor 2 Nrf2 -mediated protein quality control in cardiomyocytes

“…Therefore, it is important for a polypeptide to attain and maintain its native conformation. The native conformation that a protein acquires during its biogenesis is attained through folding of the polypeptide chain spontaneously or with the help of molecular chaperones (1). However, the biogenesis of native proteins is not a very efficient process because studies have shown that approximately one third of newly synthesized polypeptides never make to mature proteins; they are cotranslationally degraded presumably due to errors in translation and/or folding (2).…”

“…Moreover, UPS impairment results in compensatory activation of autophagy for clearing damaged proteins (19)(20)(21), whereas autophagy malfunction may impair UPS performance (22,23). The function and regulation of the UPS and the ALP as well as their interplay in cardiac diseases have been recently reviewed (1,5,7). Herein we will summarize the latest literature regarding an emerging role of Nuclear factor erythroid-2 related factor 2 (Nrf2) in the regulation of intracellular PQC as well as its potential involvement in cardiac pathology.…”