Multifunctional Roles of αB-Crystallin in Skeletal and Cardiac Muscle Homeostasis and Disease

Mitzelfelt, Katie A.; Benjamin, Ivor J.

doi:10.1007/978-3-319-16077-1_11

Cited by 3 publications

(4 citation statements)

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“…Moreover, CryAB brings protection against apoptosis through inhibiting caspase-3 activation, segregation of the antiapoptotic protein Bcl-2, and prevention of Bcl-2 translocation into the mitochondria [113]. In addition, CryAB is also inducible in response to other forms of stress such as inflammation and heat [114]. Mutations in CryAB [115], specifically the dominant R120G mutations in the CryAB gene (CryAB R120G ), lead to myopathies via reductive stress, which is responsible for cellular hypertrophy in cardiomyocytes derived from induced pluripotent stem cells [116,117].…”

Section: Oxidative Medicine and Cellular Longevitymentioning

confidence: 99%

Reductive Stress-Induced Mitochondrial Dysfunction and Cardiomyopathy

Tao

et al. 2020

Oxidative Medicine and Cellular Longevity

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The goal of this review was to summarize reported studies focusing on cellular reductive stress-induced mitochondrial dysfunction, cardiomyopathy, dithiothreitol- (DTT-) induced reductive stress, and reductive stress-related free radical reactions published in the past five years. Reductive stress is considered to be a double-edged sword in terms of antioxidation and disease induction. As many underlying mechanisms are still unclear, further investigations are obviously warranted. Nonetheless, reductive stress is thought to be caused by elevated levels of cellular reducing power such as NADH, glutathione, and NADPH; and this area of research has attracted increasing attention lately. Albeit, we think there is a need to conduct further studies in identifying more indicators of the risk assessment and prevention of developing heart damage as well as exploring more targets for cardiomyopathy treatment. Hence, it is expected that further investigation of underlying mechanisms of reductive stress-induced mitochondrial dysfunction will provide novel insights into therapeutic approaches for ameliorating reductive stress-induced cardiomyopathy.

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Section: Oxidative Medicine and Cellular Longevitymentioning

confidence: 99%

Reductive Stress-Induced Mitochondrial Dysfunction and Cardiomyopathy

Tao

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…The metastable desmin protein is a known client for HSPB5 (12)(13)(14) and is present in aggregates in patients with desminrelated (cardio)myopathy (25,26,40). Although 343delT aggregates did not colocalize with desmin in iSKMs, we wanted to examine this in BHK21 cells, which express endogenous desmin as well (26,31).…”

Section: Generation Of Ipscs For the Investigation Of 343delt-mentioning

confidence: 99%

“…24,25). These mutations are either dominant or recessive and have variable penetrance and expressivity.…”

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confidence: 99%

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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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Small heat shock proteins: Simplicity meets complexity

Haslbeck

Weinkauf

Büchner

2019

Journal of Biological Chemistry

213

218

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Edited by Norma M. Allewell Small heat shock proteins (sHsps) are a ubiquitous and ancient family of ATP-independent molecular chaperones. A key characteristic of sHsps is that they exist in ensembles of iso-energetic oligomeric species differing in size. This property arises from a unique mode of assembly involving several parts of the subunits in a flexible manner. Current evidence suggests that smaller oligomers are more active chaperones. Thus, a shift in the equilibrium of the sHsp ensemble allows regulating the chaperone activity. Different mechanisms have been identified that reversibly change the oligomer equilibrium. The promiscuous interaction with non-native proteins generates complexes that can form aggregate-like structures from which native proteins are restored by ATP-dependent chaperones such as Hsp70 family members. In recent years, this basic paradigm has been expanded, and new roles and new cofactors, as well as variations in structure and regulation of sHsps, have emerged. This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 1035. This is the fifth article in the JBC Reviews series "Molecular chaperones and protein quality control." The authors declare that they have no conflicts of interest with the contents of this article.

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Multifunctional Roles of αB-Crystallin in Skeletal and Cardiac Muscle Homeostasis and Disease

Cited by 3 publications

References 160 publications

Reductive Stress-Induced Mitochondrial Dysfunction and Cardiomyopathy

Reductive Stress-Induced Mitochondrial Dysfunction and Cardiomyopathy

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

Small heat shock proteins: Simplicity meets complexity

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