SUMOylation: a novel protein quality control modifier in the heart.

P roteins require correct folding to be functional, and this is achieved primarily with the aid of chaperones. Because protein folding is an extremely intricate and error-prone process , it is highly susceptible to failure in the presence of stress. Misfolded proteins are not only nonfunctional but they also tend to form a large mass called a preamyloid oligomer (PAO). Formation of PAO is thought to be detrimental to cells because it interferes with the function of other nearby proteins through sticky interactions, which in turn induces endoplasmic reticu-lum stress and oxidative stress, culminating in global cellular and organ dysfunction, generally referred to as proteotoxicity and proteinopathy, respectively. Increasing lines of evidence suggest that protein misfolding contributes to the pathogenesis of many forms of cardiac disease and heart failure, and in this regard, they can be classified as proteinopathies. To control protein turnover (which can be as high as ≈2% of total protein per day) and prevent accumulation of misfolded proteins, cardiomyocytes use vigorous mechanisms for protein quality control (PQC), 1 including molecular chaperones, the unfolded protein response in the ER and mitochondria, and the degradation mechanisms, namely the ubiquitin proteasome system (UPS) and autophagy (Figure). In the UPS, the 26S protea-some degrades damaged and misfolded proteins after tagging with ubiquitin to identify them for degradation. Autophagy is a bulk degradation system in which damaged proteins and organelles are degraded by lysosomal proteases. Despite the importance of PQC for the maintenance of proper function in the heart, the detailed molecular mechanisms by which the heart develops amyloid oligomers remain poorly understood, and it is not clear whether modulation of such mechanisms could be a method of treatment in patients with heart disease. In this issue of Circulation Research, Gupta et al 6 demonstrate that SUMOylation, a form of post-translational modification involving attachment of small ubiquitin-related modifier (SUMO) proteins, plays an important role in mediating PQC in cardiomyocytes by stimulating degradation through the UPS. SUMOylation is a process in which SUMO proteins are co-valently attached to specific lysine residues in target proteins, thereby regulating various aspects of protein function, including transcription, subcellular localization, DNA repair, and cell cycle. 7 Unlike the UPS, however, it does not directly degrade its target proteins. To date, 4 SUMO isoforms (SUMO1 to SUMO4) have been isolated in mammalian cells. Like ubiq-uitination, SUMOylation occurs through a series of enzymatic reactions. In the first step, SUMO precursors …