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Review
. 2020 Nov:148:89-102.
doi: 10.1016/j.yjmcc.2020.08.018. Epub 2020 Sep 10.

Under construction: The dynamic assembly, maintenance, and degradation of the cardiac sarcomere

Thomas G Martin  1 , Jonathan A Kirk  2
Affiliations
Review

Under construction: The dynamic assembly, maintenance, and degradation of the cardiac sarcomere

Thomas G Martin et al. J Mol Cell Cardiol. 2020 Nov.

Abstract

The sarcomere is the basic contractile unit of striated muscle and is a highly ordered protein complex with the actin and myosin filaments at its core. Assembling the sarcomere constituents into this organized structure in development, and with muscle growth as new sarcomeres are built, is a complex process coordinated by numerous factors. Once assembled, the sarcomere requires constant maintenance as its continuous contraction is accompanied by elevated mechanical, thermal, and oxidative stress, which predispose proteins to misfolding and toxic aggregation. To prevent protein misfolding and maintain sarcomere integrity, the sarcomere is monitored by an assortment of protein quality control (PQC) mechanisms. The need for effective PQC is heightened in cardiomyocytes which are terminally differentiated and must survive for many years while preserving optimal mechanical output. To prevent toxic protein aggregation, molecular chaperones stabilize denatured sarcomere proteins and promote their refolding. However, when old and misfolded proteins cannot be salvaged by chaperones, they must be recycled via degradation pathways: the calpain and ubiquitin-proteasome systems, which operate under basal conditions, and the stress-responsive autophagy-lysosome pathway. Mutations to and deficiency of the molecular chaperones and associated factors charged with sarcomere maintenance commonly lead to sarcomere structural disarray and the progression of heart disease, highlighting the necessity of effective sarcomere PQC for maintaining cardiac function. This review focuses on the dynamic regulation of assembly and turnover at the sarcomere with an emphasis on the chaperones involved in these processes and describes the alterations to chaperones - through mutations and deficient expression - implicated in disease progression to heart failure.

Keywords: Autophagy; Calpain; Chaperone; Proteasome; Protein quality control; Sarcomere; Sarcomerogenesis; Ubiquitin.

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Figures

Figure 1.
Figure 1.. The cardiac sarcomere and assembly of the myofilaments.
(A).Schematic diagram of the sarcomere and sarcomere-associated proteins. The sarcomere is the basic contractile unit in striated muscle with the thin actin and thick myosin myofilament proteins at its core. Sarcomeres are bounded at either end by α-actinin-rich Z-discs and are arranged sequentially to form myofibrils. (B). Simplified schematic of thin and thick filament assembly. GimC binds newly synthesized actin as it is translated by the ribosome and mediates early stages of folding. GimC passes now semi-folded actin to TriC, which assists in the assembly of the actin filament. Thin filament assembly is further supported by FHOD3, which stabilizes monomeric and filamentous actin and is crucial for actin filament nucleation and polymerization. The small heat shock proteins (heat shock protein B family, HSPBs) stabilize actin monomers and prevent protein aggregate formation. Actin capping proteins, CapZ and tropomodulin (T-Mod), bind to the ends of actin filaments and maintain stability. CapZ itself requires the BAG3/HSC70 chaperone complex to maintain its stability. Unc45 is the key chaperone for thick filament assembly and stability. It prevents myosin aggregation and assists with the folding of the myosin ATPase domain. Unc45 is a co-chaperone for HSP90, which participates in the early stages of myosin folding and myofibril assembly. The lysine methyltransferase SmyD1 is proposed to interact with the HSP90/Unc45/myosin complex.
Figure 2.
Figure 2.. Sarcomeric protein degradation in the healthy and failing heart.
(A). Schematic representation of sarcomere PQC in the healthy heart. Three protein degradation pathways are in place for the sarcomere. The calpains proteolyze sarcomere proteins and release protein monomers to be degraded by the ubiquitin proteasome system (UPS). The UPS also mediates the degradation of individual misfolded proteins. Larger protein aggregates are removed by the autophagy/lysosome pathway. (B). Schematic representation of the changes to sarcomere PQC that occur in the end-stage failing heart. Proteins misfolded from mechanical (stemming from increased afterload), thermal, oxidative, and genetic stress aggregate in the end-stage failing heart. Aberrant protein misfolding as a result of these stressors is accompanied by elevated calpain activity, which produces excess proteolysis products. Compounding the issue of proteotoxicity, the activity of the systems designed to recycle these proteins, the UPS and autophagy, are downregulated in heart failure. Together, these factors culminate in toxic levels of protein aggregation, which – presumably – contribute to the sarcomere structural disarray and mechanical dysfunction commonly found in failing myocardium. Which specific proteins aggregate and to what extent remains to be fully elucidated.
Figure 3.
Figure 3.. Chaperone-assisted selective autophagy at the sarcomere.
(A). The co-chaperone BAG3 operates as a scaffold for HSP70 and HSPB8, which bind to misfolded filamin C. The E3 ligase CHIP then ubiquitinates filamin C, allowing it to be recognized by the ubiquitin receptor P62, which facilitates the association of the CASA complex with LC3 on the autophagosome membrane. Through BAG3 this complex also associates with SYNPO-2, which mediates interaction with a SNARE protein on the autophagosome membrane that assists with autophagosome formation. Autophagosome contents are recycled via autophagosome-lysosome fusion. (B). BAG3 domains enable numerous binding activities. SYNPO2, which assists in autophagosome formation, binds to the N-terminal WW domain. Several HSPBs bind to two IPV motifs and the BAG domain associates with the ATPase domain of HSP70/HSC70.
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