HSPB1 Enhances SIRT2-Mediated G6PD Activation and Promotes Glioma Cell Proliferation

Ye, Hongxing; Huang, Hongyang; Cao, Fei; Chen, Mantao; Zheng, Xianliang; Zhan, Renya

doi:10.1371/journal.pone.0164285

Cited by 49 publications

(37 citation statements)

References 22 publications

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“…This cysteine is highly conserved in HSP27 orthologs but not found in other mammalian sHSPs 21 , implying that it plays an important and specific role in regulating function. Accordingly, the presence of this disulphide bond impacts on the activity of HSP27 in vitro [22][23][24] , and on the resistance of cells to oxidative stress 20,21,25,26 . Intriguingly, variants of HSP27 that have an increased tendency to form monomers display hyperactivity both in vitro and in vivo 27,28 .…”

Section: Introductionmentioning

confidence: 99%

Local unfolding of the HSP27 monomer regulates chaperone activity

Alderson

Roche

Gastall

et al. 2018

Preprint

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The small heat-shock protein HSP27 is a redox-sensitive molecular chaperone that is expressed throughout the human body. Here we describe redox-induced changes to the structure, dynamics, and function of HSP27 and its conserved -crystallin domain, and provide the first structural characterization of a small heat-shock protein monomer. While HSP27 assembles into oligomers, we show that the transiently populated monomers released upon reduction are highly active chaperones in vitro, but are kinetically unstable and susceptible to uncontrolled aggregation. By using relaxation dispersion and high-pressure nuclear magnetic resonance spectroscopy, we reveal that the pair of strands that mediate dimerization become partially disordered in the monomer. Strikingly, we note that numerous HSP27 mutations associated with inherited neuropathies cluster to this unstructured region. The high degree of sequence conservation in the -crystallin domain amongst mammalian sHSPs suggests that partially unfolded monomers may be a general, functional feature of these molecular chaperones.

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Section: Introductionmentioning

confidence: 99%

Local unfolding of the HSP27 monomer regulates chaperone activity

Alderson

Roche

Gastall

et al. 2018

Preprint

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“…The sHSPs participate in the proteome integrity by binding to the hydrophobic regions of misfolded and non-native proteins in stressful conditions. Besides their canonical function in proteostasis, sHSPs have been involved in an increasing number of cellular functions in stress and physiological conditions such as cellular differentiation and proliferation, translation, oxidative stress regulation, cytoskeleton stabilisation, apoptosis, and autophagy [ 1 , 3 , 19 , 33 , 39 , 59 , 86 ]. Interestingly, mutations in HSPB1 and αB-crystallin, two other members of the same sHSP family, have also been associated with inherited peripheral neuropathies [ 11 , 24 , 27 , 48 , 63 , 68 ], and distal myopathy, respectively [ 28 , 53 , 82 ].…”

Section: Introductionmentioning

confidence: 99%

A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8

et al. 2017

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Mutations in the small heat shock protein B8 gene (HSPB8/HSP22) have been associated with distal hereditary motor neuropathy, Charcot–Marie–Tooth disease, and recently distal myopathy. It is so far not clear how mutant HSPB8 induces the neuronal and muscular phenotypes and if a common pathogenesis lies behind these diseases. Growing evidence points towards a role of HSPB8 in chaperone-associated autophagy, which has been shown to be a determinant for the clearance of poly-glutamine aggregates in neurodegenerative diseases but also for the maintenance of skeletal muscle myofibrils. To test this hypothesis and better dissect the pathomechanism of mutant HSPB8, we generated a new transgenic mouse model leading to the expression of the mutant protein (knock-in lines) or the loss-of-function (functional knock-out lines) of the endogenous protein Hspb8. While the homozygous knock-in mice developed motor deficits associated with degeneration of peripheral nerves and severe muscle atrophy corroborating patient data, homozygous knock-out mice had locomotor performances equivalent to those of wild-type animals. The distal skeletal muscles of the post-symptomatic homozygous knock-in displayed Z-disk disorganisation, granulofilamentous material accumulation along with Hspb8, αB-crystallin (HSPB5/CRYAB), and desmin aggregates. The presence of the aggregates correlated with reduced markers of effective autophagy. The sciatic nerve of the homozygous knock-in mice was characterized by low autophagy potential in pre-symptomatic and Hspb8 aggregates in post-symptomatic animals. On the other hand, the sciatic nerve of the homozygous knock-out mice presented a normal morphology and their distal muscle displayed accumulation of abnormal mitochondria but intact myofiber and Z-line organisation. Our data, therefore, suggest that toxic gain-of-function of mutant Hspb8 aggregates is a major contributor to the peripheral neuropathy and the myopathy. In addition, mutant Hspb8 induces impairments in autophagy that may aggravate the phenotype.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1756-0) contains supplementary material, which is available to authorized users.

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“…This cysteine is highly conserved in HSP27 orthologs but not found in other mammalian sHSPs 14 , implying that it plays an important functional role. Accordingly, the presence of this disulphide bond impacts on the activity of HSP27 in vitro [15][16][17] and on the resistance of cells to oxidative stress 13,14,18,19 . Like other mammalian sHSPs, HSP27 assembles to form a wide range of oligomers 20 whose constituent monomers and dimers freely exchange between oligomers 21,22 .…”

mentioning

confidence: 99%

Local unfolding of the HSP27 monomer regulates chaperone activity

et al. 2019

View full text Add to dashboard Cite

The small heat-shock protein HSP27 is a redox-sensitive molecular chaperone that is expressed throughout the human body. Here, we describe redox-induced changes to the structure, dynamics, and function of HSP27 and its conserved α-crystallin domain (ACD). While HSP27 assembles into oligomers, we show that the monomers formed upon reduction are highly active chaperones in vitro, but are susceptible to self-aggregation. By using relaxation dispersion and high-pressure nuclear magnetic resonance (NMR) spectroscopy, we observe that the pair of β-strands that mediate dimerisation partially unfold in the monomer. We note that numerous HSP27 mutations associated with inherited neuropathies cluster to this dynamic region. High levels of sequence conservation in ACDs from mammalian sHSPs suggest that the exposed, disordered interface present in free monomers or oligomeric subunits may be a general, functional feature of sHSPs.

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HSPB1 Enhances SIRT2-Mediated G6PD Activation and Promotes Glioma Cell Proliferation

Cited by 49 publications

References 22 publications

Local unfolding of the HSP27 monomer regulates chaperone activity

Local unfolding of the HSP27 monomer regulates chaperone activity

A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8

Local unfolding of the HSP27 monomer regulates chaperone activity

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