Small heat-shock proteins and their role in mechanical stress

Collier, M; Benesch, Justin L. P.

doi:10.1007/s12192-020-01095-z

Cited by 46 publications

(44 citation statements)

References 115 publications

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“…Accordingly, interference with HSPB7 expression in zebrafish and human cardiomyocytes also results in increased load by damaged proteins and stimulation of autophagic pathways [ 50 ]. Further studies are necessary to resolve the cause for its strongly reduced expression in our Hom mice, and to elucidate its precise role, both in actin-based assembly and regulation of autophagic pathways [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Schuld

Orfanos

Chevessier

et al. 2020

acta neuropathol commun

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Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-like domain 24. We previously characterized “knock-in” mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: in comparison to wildtype animals (i) the expression level of FLNc protein is drastically reduced; (ii) mutant FLNc is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack Bcl2-associated athanogene 3 (BAG3) protein; (iv) the expression of heat shock protein beta-7 (HSPB7) is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective FLNc dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative, more amino-terminally located dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that FLNc is important for mechanosensing in the context of Z-disc stabilization and maintenance.

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Section: Discussionmentioning

confidence: 99%

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Schuld

Orfanos

Chevessier

et al. 2020

acta neuropathol commun

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“…Included in the Hsp family are small heat shock proteins (sHsps), which are ubiquitously expressed regulators of cellular protein folding [ 30 ]. The high expression of sHsps in the heart has been reported, where they are implicated in the maintenance of normal cardiac function and regulation of the cardiac stress response [ 50 , 51 ].…”

Section: An Emerging Field: Heat Shock Protein and Molecular Chapementioning

confidence: 99%

Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications

Spracklen

Chakafana

Schwartz

et al. 2021

Genes

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Peripartum cardiomyopathy (PPCM) is a condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. Over the last decade, genetic advances in heritable cardiomyopathy have provided new insights into the role of genetics in PPCM. In this review, we summarise current knowledge of the genetics of PPCM and potential avenues for further research, including the role of molecular chaperone mutations in PPCM. Evidence supporting a genetic basis for PPCM has emanated from observations of familial disease, overlap with familial dilated cardiomyopathy, and sequencing studies of PPCM cohorts. Approximately 20% of PPCM patients screened for cardiomyopathy genes have an identified pathogenic mutation, with TTN truncations most commonly implicated. As a stress-associated condition, PPCM may be modulated by molecular chaperones such as heat shock proteins (Hsps). Recent studies have led to the identification of Hsp mutations in a PPCM model, suggesting that variation in these stress-response genes may contribute to PPCM pathogenesis. Although some Hsp genes have been implicated in dilated cardiomyopathy, their roles in PPCM remain to be determined. Additional areas of future investigation may include the delineation of genotype-phenotype correlations and the screening of newly-identified cardiomyopathy genes for their roles in PPCM. Nevertheless, these findings suggest that the construction of a family history may be advised in the management of PPCM and that genetic testing should be considered. A better understanding of the genetics of PPCM holds the potential to improve treatment, prognosis, and family management.

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“…13 Studies have shown that chaperones like α β crystallin or calreticulin has played crucial role in deciding mechanical properties of cell, like resilience of cell adhesion, cell spreading, by regulating expression of key focal adhesion proteins. 13,14 Small heat shock proteins have also been observed to regulate chronic biomechanical stress in heart tissue by regulating dynamics of key FA protein like actin and filamin C. 17 Additionally, tension-induced ubiquitylation of filamin A promotes chaperone-assisted autophagy which in turn dictate the role of chaperones in focal adhesion assembly. 35,36 However, the underlying molecular mechanism of these chaperone interactions, during mechanotransduction, has not been reported yet.…”

Section: Discussionmentioning

confidence: 99%

Real time observation of chaperone-modulated talin mechanics with single molecule resolution

Banerjee

Chaudhuri

Chakraborty

et al. 2021

Preprint

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Recent single molecule studies have recognized talin as a mechanosensitive hub in focal adhesion, where its function is strongly regulated by mechanical force. For instance, at low force (less than 5pN), folded talin binds RIAM for integrin activation; whereas at high force (more than 5pN), it unfolds to activate vinculin binding for focal adhesion stabilization. Being a cytoplasmic large protein, talin must interact with various chaperones, however the role of chaperones on talin mechanics is unknown. To address this question, we investigated the force response of a mechanically stable talin domain, with a set of well-known holdase and foldase chaperones, using a single molecule magnetic tweezers technology. Our findings demonstrate a novel mechanical role of chaperones. We found holdase chaperones reduce the mechanical stability of the protein to ~6 pN, while the foldase chaperone increases it up to ~15 pN. The alteration in mechanical stability ascribes to the underlying molecular mechanism where the chaperones directly reshape the energy landscape of talin. For example, unfoldase chaperone (DnaK) decreases the unfolding barrier height from 26.8 to 21.69 kBT and increases the refolding barrier from 3.49 to 11.31 kBT. In contrast, foldase chaperone (DsbA) increases the unfolding barrier to 33.46 kBT and decreases the refolding barrier to 0.44 kBT. The quantitative mapping of the chaperone-induced free energy landscape of talin directly shows that chaperones could perturb the focal adhesion dynamics, which in turn can influence downstream signaling cascades in diverse cellular processes.

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Small heat-shock proteins and their role in mechanical stress

Cited by 46 publications

References 115 publications

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications

Real time observation of chaperone-modulated talin mechanics with single molecule resolution

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