Challenging muscle homeostasis uncovers novel chaperone interactions in Caenorhabditis elegans

Frumkin, Anna; Dror, Shiran; Pokrzywa, Wojciech; Bar-Lavan, Yael; Karady, Ido; Hoppe, Thorsten; Ben‐Zvi, Anat

doi:10.3389/fmolb.2014.00021

Cited by 22 publications

(27 citation statements)

References 57 publications

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“…Nevertheless, it is noteworthy that Unc45 was linked to muscle differentiation and myosin assembly in the nematode Caenorhabditis elegans (55,56), an organism that has p23 but no Aarsd1 ortholog. Moreover, in an Unc45 mutant of the same organism, Hsp90 and other cochaperones are required for muscle integrity and motility (57).…”

Section: Discussionmentioning

confidence: 99%

A Remodeled Hsp90 Molecular Chaperone Ensemble with the Novel Cochaperone Aarsd1 Is Required for Muscle Differentiation

Echeverria

Briand

Picard

2016

Molecular and Cellular Biology

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Hsp90 is the ATP-consuming core component of a very abundant molecular chaperone machine that handles a substantial portion of the cytosolic proteome. Rather than one machine, it is in fact an ensemble of molecular machines, since most mammalian cells express two cytosolic isoforms of Hsp90 and a subset of up to 40 to 50 cochaperones and regulate their interactions and functions by a variety of posttranslational modifications. We demonstrate that the Hsp90 ensemble is fundamentally remodeled during muscle differentiation and that this remodeling is not just a consequence of muscle differentiation but possibly one of the drivers to accompany and to match the vast proteomic changes associated with this process. As myoblasts differentiate into myotubes, Hsp90␣ disappears and only Hsp90␤ remains, which is the only isoform capable of interacting with the novel musclespecific Hsp90 cochaperone Aarsd1L. Artificially maintaining Hsp90␣ or knocking down Aarsd1L expression interferes with the differentiation of C2C12 myotubes. During muscle differentiation, Aarsd1L replaces the more ubiquitous cochaperone p23 and in doing so dampens the activity of the glucocorticoid receptor, one of the Hsp90 clients relevant to muscle functions. This cochaperone switch protects muscle cells against the inhibitory effects of glucocorticoids and may contribute to preventing muscle wasting induced by excess glucocorticoids. H sp90 is a highly abundant molecular chaperone, including in nonstressed cells, which is required for the maturation, stability, activity, and/or degradation of a substantial portion of the proteome (1-5) (for a regularly updated list of Hsp90 interactors, see http://www.picard.ch/downloads/Hsp90interactors.pdf). To its clients, the Hsp90 dimer offers a moving platform whose complex choreography involves ATP hydrolysis, huge conformational changes, and dynamic interactions with a large cohort of cochaperones (3, 6-11). The cochaperones regulate and are part of the Hsp90 cycle (3,(8)(9)(10)(11), and some may act as client specificity factors (12, 13). With 40 to 50 cochaperones, far more have been reported (see http://www.picard.ch/downloads/Hsp90facts.pdf) than the ones that have been extensively characterized as interacting with Hsp90 as part of the core cycle. Moreover, Hsp90 and cochaperones are extensively regulated by posttranslational modifications (see, for example, references 14-17), and Hsp90 is present in excess over any individual cochaperone. Hence, the Hsp90 molecular chaperone machine constitutes in fact an ensemble of complexes. These complexes dynamically interchange and are fashioned by the cell specificity of signaling and cochaperone expression patterns.One of the most extensively characterized components of the Hsp90 core machinery is the cochaperone p23 (18-20), encoded by the PTGES3 gene in mammals. This small acidic protein binds and stabilizes the ATP-bound state of Hsp90 (19-23). p23 binding, which is disrupted by Hsp90 inhibitors competing with ATP and by hyperacetylation of Hsp90, promotes a ...

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Section: Discussionmentioning

confidence: 99%

A Remodeled Hsp90 Molecular Chaperone Ensemble with the Novel Cochaperone Aarsd1 Is Required for Muscle Differentiation

Echeverria

Briand

Picard

2016

Molecular and Cellular Biology

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“…However, this activation is also regulated by cell non-autonomous signals that can inhibit or induce a heat shock response regardless of protein damage [14]. Although chaperone over-expression often alleviates misfolded protein-associated toxicity [2, 15], accumulation of chaperones and activation of the heat shock response can also be detrimental to organismal health [12, 16–22], possibly by disrupting sub-networks of chaperones and co-chaperones [23–25]. …”

Section: Introductionmentioning

confidence: 99%

“…For instance, myosin folding and assembly requires the coordinated functions of the Hsp90 chaperone machinery (Hsp90 and its co-chaperones STI1-AHA1-P23) and the myosin-specific chaperone UNC-45 [25, 32, 38]. Moreover, there are examples of muscle-specific diseases that are associated with mutations in a ubiquitously expressed chaperone, such as DNAJB6 associated with the limb-girdle muscular dystropy [18, 39].…”

Section: Introductionmentioning

confidence: 99%

A Differentiation Transcription Factor Establishes Muscle-Specific Proteostasis in Caenorhabditis elegans

et al. 2016

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Safeguarding the proteome is central to the health of the cell. In multi-cellular organisms, the composition of the proteome, and by extension, protein-folding requirements, varies between cells. In agreement, chaperone network composition differs between tissues. Here, we ask how chaperone expression is regulated in a cell type-specific manner and whether cellular differentiation affects chaperone expression. Our bioinformatics analyses show that the myogenic transcription factor HLH-1 (MyoD) can bind to the promoters of chaperone genes expressed or required for the folding of muscle proteins. To test this experimentally, we employed HLH-1 myogenic potential to genetically modulate cellular differentiation of Caenorhabditis elegans embryonic cells by ectopically expressing HLH-1 in all cells of the embryo and monitoring chaperone expression. We found that HLH-1-dependent myogenic conversion specifically induced the expression of putative HLH-1-regulated chaperones in differentiating muscle cells. Moreover, disrupting the putative HLH-1-binding sites on ubiquitously expressed daf-21(Hsp90) and muscle-enriched hsp-12.2(sHsp) promoters abolished their myogenic-dependent expression. Disrupting HLH-1 function in muscle cells reduced the expression of putative HLH-1-regulated chaperones and compromised muscle proteostasis during and after embryogenesis. In turn, we found that modulating the expression of muscle chaperones disrupted the folding and assembly of muscle proteins and thus, myogenesis. Moreover, muscle-specific over-expression of the DNAJB6 homolog DNJ-24, a limb-girdle muscular dystrophy-associated chaperone, disrupted the muscle chaperone network and exposed synthetic motility defects. We propose that cellular differentiation could establish a proteostasis network dedicated to the folding and maintenance of the muscle proteome. Such cell-specific proteostasis networks can explain the selective vulnerability that many diseases of protein misfolding exhibit even when the misfolded protein is ubiquitously expressed.

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“…Knockdown of any of these three factors in the unc-45 background resulted in motility defects and myofibril disorganization. The cochaperones form discrete complexes with Hsp90 and do not bind UNC-45 directly; they localized in a striated pattern in the sarcomere, thus supporting their role in the myosin folding network 13 .…”

Section: New Physiological Roles For Hsp90mentioning

confidence: 88%

The Hsp90 ensemble: coordinated Hsp90–cochaperone complexes regulate diverse cellular processes

Schwenkert

Hugel

Cox

2014

Nat Struct Mol Biol

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Challenging muscle homeostasis uncovers novel chaperone interactions in Caenorhabditis elegans

Cited by 22 publications

References 57 publications

A Remodeled Hsp90 Molecular Chaperone Ensemble with the Novel Cochaperone Aarsd1 Is Required for Muscle Differentiation

A Remodeled Hsp90 Molecular Chaperone Ensemble with the Novel Cochaperone Aarsd1 Is Required for Muscle Differentiation

A Differentiation Transcription Factor Establishes Muscle-Specific Proteostasis in Caenorhabditis elegans

The Hsp90 ensemble: coordinated Hsp90–cochaperone complexes regulate diverse cellular processes

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