Untying the knot: protein quality control in inherited cardiomyopathies

Abstract

Mutations in genes encoding sarcomeric proteins are the most important causes of inherited cardiomyopathies, which are a major cause of mortality and morbidity worldwide. Although genetic screening procedures for early disease detection have been improved significantly, treatment to prevent or delay mutation-induced cardiac disease onset is lacking. Recent findings indicate that loss of protein quality control (PQC) is a central factor in the disease pathology leading to derailment of cellular protein homeostasis. Loss of PQC includes impairment of heat shock proteins, the ubiquitin-proteasome system, and autophagy. This may result in accumulation of misfolded and aggregation-prone mutant proteins, loss of sarcomeric and cytoskeletal proteins, and, ultimately, loss of cardiac function. PQC derailment can be a direct effect of the mutation-induced activation, a compensatory mechanism due to mutation-induced cellular dysfunction or a consequence of the simultaneous occurrence of the mutation and a secondary hit. In this review, we discuss recent mechanistic findings on the role of proteostasis derailment in inherited cardiomyopathies, with special focus on sarcomeric gene mutations and possible therapeutic applications.

Keywords: Autophagy; Cardiomyopathy; Heat shock proteins; Protein quality control; Sarcomeric mutation; Ubiquitin-proteasome system.

Fig. 1

Collaboration of the protein quality control components. Stress leads to misfolding of proteins, which may result in abnormal interaction and subsequent aggregation. Small HSPs (white/gray rectangle) and HSPs with ATPase activity (blue moon shape with black rectangle) prevent aggregation formation by binding to the hydrophobic surfaces of misfolded proteins. They either refold the misfolded proteins to its native structure or initiate its polyubiquitination (Ub, orange hexagon). Misfolded proteins with polyubiquitin chains linked to lysine 48 (K48) are mainly degraded by the proteasome. Misfolded proteins carrying K63-linked polyubiquitin chains and aggregated proteins enter the autophagic pathway

Fig. 2

Chaperone cofactor binding determines the heat shock protein (HSP) function. Small HSPs (white/gray rectangle) and HSPs with ATPase activity (blue moon shape with black rectangle) bind to the misfolded protein to stabilize it. Dependent on the chaperone cofactors (green circles or turquoise squares), the misfolded protein gets either refolded or ubiquitinated for subsequent degradation. If refolding is impossible, the chaperone cofactors can be exchanged to promote degradation. In case of ubiquitination, the chaperone cofactors can switch off the HSP refolding activity by blocking the ATPase activity and, together with HSPs, assist in clearance of the misfolded protein via the degradation pathways

Fig. 3

Effects of sarcomeric gene mutations on the protein quality control (PQC) system. Sarcomeric gene mutations can directly derail PQC function leading to cardiomyocyte dysfunction. PQC derailments in cardiomyopathies (CMs) can also be a compensatory mechanism to counteract cardiomyocyte dysfunction caused by the sarcomeric gene mutation. The secondary-hit hypothesis suggests that the PQC of cardiomyocytes carrying a sarcomeric gene mutation is more prone to derail in response to additional cellular stressors, thereby resulting in cardiomyocyte dysfunction