Chaperones and the Proteasome System: Regulating the Construction and Demolition of Striated Muscle

Abstract

Protein folding factors (chaperones) are required for many diverse cellular functions. In striated muscle, chaperones are required for contractile protein function, as well as the larger scale assembly of the basic unit of muscle, the sarcomere. The sarcomere is complex and composed of hundreds of proteins and the number of proteins and processes recognized to be regulated by chaperones has increased dramatically over the past decade. Research in the past ten years has begun to discover and characterize the chaperones involved in the assembly of the sarcomere at a rapid rate. Because of the dynamic nature of muscle, wear and tear damage is inevitable. Several systems, including chaperones and the ubiquitin proteasome system (UPS), have evolved to regulate protein turnover. Much of our knowledge of muscle development focuses on the formation of the sarcomere but recent work has begun to elucidate the requirement and role of chaperones and the UPS in sarcomere maintenance and disease. This review will cover the roles of chaperones in sarcomere assembly, the importance of chaperone homeostasis and the cooperation of chaperones and the UPS in sarcomere integrity and disease.

Intracellular Localization in Zebrafish Muscle and Conserved Sequence Features Suggest Roles for Gelatinase A Moonlighting in Sarcomere Maintenance

“…The M-band of the sarcomere is rich in kinases and phosphatases that are known to function in regulating the turnover of sarcomeric proteins [70], although the specific mechanisms they regulate remain somewhat obscure. This suggests to us that gelatinase A may play a role in maintaining the proteostasis of the sarcomere, possibly contributing to the complex system mediating recycling of surplus and damaged components of the thick filament during muscle cell development and in response to exhaustive exercise [71][72][73]. The phosphorylation status of gelatinase A may therefore indicate the physiological status of the myocyte, and the zebrafish is emerging as an excellent model system for investigating these sorts of questions regarding muscle cell development and physiology [74,75].…”

Assembly and Maintenance of Sarcomere Thin Filaments and Associated Diseases

“…Single protein degradation happens through the Ubiquitin-Proteasome System (UPS), following isolation from the myofiber by calpains in most cases. The UPS is one of the major quality control pathways for thin filament maintenance and turnover with many proteins destined for degradation by the proteasome [75]. This section will focus on factors that monitor and target thin filament and thin filament associated proteins for turnover (e.g., Bag3).…”

“…E3 ubiquitin ligases (MuRF(s)) recognize damaged client proteins and transport them to E1 and E2 ligases for ubiquitination and subsequent degradation by the proteasome. For a recent detailed review of the UPS in muscle, see [75].…”

“…The 26S proteasome is the final destination for proteins targeted by the ubiquitin-proteasome system [75,106,107]. Although no calpain or E3 ligase that recognizes troponin C has been identified to date, troponin C is degraded by the 26S proteasome [80,106].…”

Mutational and functional study of Tuberous Sclerosis Complex 1 and 2 genes (TSC1 and TSC2)

“…Among the systems that have evolved to regulate protein turnover, the most well-known are chaperones. To achieve the correct tertiary and quaternary structure, protein folding factors (chaperones) are required for many proteins (Carlisle, Prill et al 2017).…”