PKG Primes the Proteasome

Abstract

Proteostasis, the precisely orchestrated balance between protein synthesis and degradation, plays a critical role in the maintenance of cell function. This is particularly the case for postmitotic cells such as cardiomyocytes and neurons, which rarely re-enter the cell cycle to divide and hence survive for decades. Disease-related stress can promote dysregulation of proteostasis, leading to accumulation of damaged or misfolded proteins as toxic aggregates capable of triggering cell death.1,2 Indeed, in both dilated cardiomyopathy and ischemic heart disease, perturbations in proteostasis are evidenced by accumulation of polyubiquitinated proteins.3 Additionally, genetic disorders that lead to aggregate formation can trigger cardiomyopathy.4 For example, specific mutations in the coding region of the molecular chaperone αB-crystallin (CryAB) disrupt its chaperone function, leading to a distinctive myofibrillar myopathy characterized by accumulation of toxic aggregates in cardiac myocytes reminiscent of Alzheimer disease or polyglutamine expansion disorders. Article see p 365 Cells can be protected from accumulation of abnormal protein aggregates by either a decrease in their formation or an increase in their clearance. Protein aggregate clearance is accomplished by 2 major catabolic processes: the ubiquitin proteasome pathway (UPP) or the autophagy-lysosomal pathway (Figure 1). Inhibition of either pathway provokes increases in toxic, intracellular aggregates that can promote disease pathogenesis. Figure 1. Damaged or misfolded proteins are targeted primarily for degradation by the ubiquitin proteasomal pathway (UPP). When an excess of these proteins accumulates, they aggregate and are degraded by autophagic pathways. If misfolded proteins continue to accumulate, they can be ultimately sequestered by the cell into ubiquitin-rich cytoplasmic inclusions called aggresomes. Autophagy is a highly conserved catabolic process underlying bulk removal of cytoplasmic proteins and organelles. Autophagy acts as an adaptive response both under conditions of starvation, where recycling of intracellular contents is required to replenish life-sustaining nutrients, and in the setting of …