Human myocytes are protected from titin aggregation-induced stiffening by small heat shock proteins

Kötter, Sebastian; Unger, Andreas; Hamdani, Nazha; Lang, Patrick; Vorgerd, Matthias; Nagel-Steger, Luitgard; Linke, Wolfgang A.

doi:10.1085/jgp.1432oia1

Cited by 8 publications

(16 citation statements)

References 42 publications

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“…The 2 sHSPs bind to Ig domain-enriched segments of the titin spring, including the proximal-Ig region and the N2-A element, but not to the intrinsically disordered PEVK domain ( Figure 2B). 57,58 The sHSPs also bind to the N2-B element, 57,58 where αB-crystallin mechanically stabilizes the N2-Bus 59 ( Figure 3) and, together with HSP27, could help organize macromolecular complexes. 58 In the presence of αB-crystallin, titin-Ig domains show a reduced probability of unfolding in vitro.…”

Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

“…57,58 The sHSPs also bind to the N2-B element, 57,58 where αB-crystallin mechanically stabilizes the N2-Bus 59 ( Figure 3) and, together with HSP27, could help organize macromolecular complexes. 58 In the presence of αB-crystallin, titin-Ig domains show a reduced probability of unfolding in vitro. 57,59 However, of particular physiological relevance is that the interaction of sHSPs with I-band titin is much enhanced by factors that increase titindomain unfolding, such as stretch and expression of the stiff N2B isoform.…”

Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

“…57,59 However, of particular physiological relevance is that the interaction of sHSPs with I-band titin is much enhanced by factors that increase titindomain unfolding, such as stretch and expression of the stiff N2B isoform. 58 Unfolded proteins typically expose cryptic hydrophobic sites and risk aggregation and loss of function. The unfolded Ig regions of titin in cardiomyocytes, however, are protected against aggregation by the sHSPs, and both the Ig-aggregation propensity and the sHSP-mediated protection against it are enhanced by acidic stress (Figure 3).…”

Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

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Gigantic Business

Linke

Hamdani

2014

Circulation Research

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292

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With every heartbeat, our cardiomyocytes are exposed to variable degrees of stress and strain of both internal and external origin. The unique mechanical properties of these myocytes are determined by the sarcomeric cytoskeleton. The actin (thin) and myosin (thick) filaments of the sarcomere are mainly relevant for active force generation, whereas the titin filaments determine sarcomeric viscoelasticity. The giant protein titin, which is the focus of this review, has various roles beyond viscoelastic force generation 1-3 : (1) it keeps the thick filaments centered in the sarcomere, allowing optimum active force development; (2) it is important for the assembly of the sarcomeres; (3) it participates in mechano-chemical signaling events via some of its binding partners; and (4) it may be crucial for the length-dependent activation of the contractile apparatus, which underlies the Frank-Starling law. During the past decade, we have learned that titin elasticity is highly variable in the developing and the adult healthy heart and that it can be pathologically altered in heart disease. These alterations greatly affect the extensibility and the diastolic passive stiffness of myocardium and presumably also the mechanosensitivity. Moreover, TTN, which encodes the titin protein, has been recognized as a major human disease gene. In this context, the properties and functions of cardiac titin have become of interest in the continuing search for the molecular origins of human heart disease and the identification of novel potential targets for therapeutic intervention. In our review, we begin with a short clinical perspective establishing the link between diastolic stiffness and titin and briefly compare the importance of titin versus collagen for myocardial passive stiffness. We then cover some details of titin protein structure and elasticity, before summarizing how titin-binding partners affect titin properties and broaden the range of titin functions, with a special focus on the standing of titin in pathways of protein quality control. We continue with a current overview of titin mutations in human skeletal muscle and heart disease. The remainder of the review deals with the contribution of titin to diastolic stiffness and how it is modulated in normal and failing hearts by mechanisms such as titin-isoform switching, titin phosphorylation (including heart failure [HF]-related alterations of it), and oxidative modifications. Clinical Context: Diastolic Function and Diastolic AbnormalitiesDiastolic function has moved into the focus of HF research, because an increasing number of patients with HF (≥50%) present with diastolic rather than systolic dysfunction. 4 Common abnormalities of diastolic function include impaired left ventricular (LV) relaxation, decreased LV distensibility, increased LV end-diastolic stiffness, and pericardial and right ventricular constraint. These abnormalities have been suggested to be contributing factors in diastolic HF or HF with a preserved ejection fraction (HFpEF).5 HFpEF is accompanied by ...

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Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

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Gigantic Business

Linke

Hamdani

2014

Circulation Research

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292

232

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“…of three independent experiments. protein quality control, differentiation, and maintenance in muscle cells (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Loss of these or other functions of HSPB5 may leave myotubes vulnerable to stress, prone to muscle breakdown with increased usage, and/or have an impact on regeneration of skeletal muscle from satellite cells.…”

Section: Discussionmentioning

confidence: 99%

“…In striated muscle, HSPB5 acts as a chaperone for important structural client proteins, including desmin (12)(13)(14), titin (15)(16)(17)(18), and actin (14,19), a property that becomes particularly important under conditions of pathology or stress. HSPB5/ HSPB2 double knockout (DKO) mice exhibit progressive skeletal myopathy throughout life (20), with an impact on cardiac muscle only observed under conditions of exogenous stress (21,22).…”

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confidence: 99%

The Human 343delT HSPB5 Chaperone Associated with Early-onset Skeletal Myopathy Causes Defects in Protein Solubility

Mitzelfelt

Limphong

Choi

et al. 2016

Journal of Biological Chemistry

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Mutations of HSPB5 (also known as CRYAB or ␣B-crystallin), a bona fide heat shock protein and molecular chaperone encoded by the HSPB5 (crystallin, alpha B) gene, are linked to multisystem disorders featuring variable combinations of cataracts, cardiomyopathy, and skeletal myopathy. This study aimed to investigate the pathological mechanisms involved in an earlyonset myofibrillar myopathy manifesting in a child harboring a homozygous recessive mutation in HSPB5, 343delT. To study HSPB5 343delT protein dynamics, we utilize model cell culture systems including induced pluripotent stem cells derived from the 343delT patient (343delT/343delT) along with isogenic, heterozygous, gene-corrected control cells (WT KI/ 343delT) and BHK21 cells, a cell line lacking endogenous HSPB5 expression. 343delT/343delT and WT KI/343delT-induced pluripotent stem cell-derived skeletal myotubes and cardiomyocytes did not express detectable levels of 343delT protein, contributable to the extreme insolubility of the mutant protein. Overexpression of HSPB5 343delT resulted in insoluble mutant protein aggregates and induction of a cellular stress response. Co-expression of 343delT with WT prevented visible aggregation of 343delT and improved its solubility. Additionally, in vitro refolding of 343delT in the presence of WT rescued its solubility. We demonstrate an interaction between WT and 343delT both in vitro and within cells. These data support a loss-of-function model for the myopathy observed in the patient because the insoluble mutant would be unavailable to perform normal functions of HSPB5, although additional gain-of-function effects of the mutant protein cannot be excluded. Additionally, our data highlight the solubilization of 343delT by WT, concordant with the recessive inheritance of the disease and absence of symptoms in carrier individuals.HSPB5 (also known as CRYAB or ␣B-crystallin) is a small molecular weight heat shock protein encoded by the HSPB5 (crystallin, alpha B) gene and functions as a molecular chaperone. Its promoter contains a heat shock element, a stress-responsive binding site of heat shock transcription factor 1 (HSF1), that functionally up-regulates the expression of HSPB5. Increased levels of HSPB5 can then go on to provide

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A Rising Titan:TTNReview and Mutation Update

2014

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The 364 exon TTN gene encodes titin (TTN), the largest known protein, which plays key structural, developmental, mechanical, and regulatory roles in cardiac and skeletal muscles. Prior to next-generation sequencing (NGS), routine analysis of the whole TTN gene was impossible due to its giant size and complexity. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. In the last months, due to the widespread use of NGS, TTN is emerging as a major gene in human-inherited disease. So far, 127 TTN disease-causing mutations have been reported in patients with at least 10 different conditions, including isolated cardiomyopathies, purely skeletal muscle phenotypes, or infantile diseases affecting both types of striated muscles. However, the identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance, and correlation with the phenotype of TTN sequence changes. In this review, we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern, and phenotype-genotype correlations, alongside with their implications for basic research and for human health.

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Human myocytes are protected from titin aggregation-induced stiffening by small heat shock proteins

Abstract: Abbreviations used in this paper: DCM, dilated cardiomyopathy; Ig, immunoglobulin-like; LGMD2A, limb girdle muscular dystrophy type 2A; sHSPs, small heat shock proteins; SL, sarcomere length.

Cited by 8 publications

References 42 publications

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The Human 343delT HSPB5 Chaperone Associated with Early-onset Skeletal Myopathy Causes Defects in Protein Solubility

A Rising Titan:TTNReview and Mutation Update

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