Two mammalian UNC-45 isoforms are related to distinct cytoskeletal and muscle-specific functions

Price, Maureen G.; Landsverk, Megan; Barral, José M.; Epstein, Henry F.

doi:10.1242/jcs.00108

Cited by 132 publications

(163 citation statements)

References 55 publications

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“…Overall, cells lacking GCUNC45 also showed marked morphological changes, becoming more rounded and having less cytoplasmic mass. These morphological changes may reflect a specific role for GCUNC45 in recruiting the Hsp90␤ machine to chaperones and organizing the cytoskeleton myosin (12,20). Hsp90 has already been shown to interact with actin and tubulin, and Hsp90-GR complexes use microtubules to migrate throughout the cytoplasm (3,21).…”

Section: Resultsmentioning

confidence: 99%

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GCUNC45 Is the First Hsp90 Co-chaperone to Show α/β Isoform Specificity

Chadli

Felts

Toft

2008

Journal of Biological Chemistry

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Hsp90 is an essential molecular chaperone required for the normal functioning of many key regulatory proteins in eukaryotic cells. Vertebrates have two closely related isoforms of cytosolic Hsp90 (Hsp90␣ and Hsp90␤). However, specific functions for each isoform are largely unknown, and no Hsp90 co-chaperone has been reported to distinguish between the two isoforms. In this study, we show that the Hsp90 co-chaperone GCUNC45 bound preferentially to the ␤ isoform of Hsp90 in vitro. GCUNC45 efficiently blocked the progression of progesterone receptor chaperoning in an in vitro functional system when Hsp90␤ was used, but did so with much less efficacy when Hsp90␣ was used. Knockdown experiments in HeLa cells showed that GCUNC45 is required for the normal cellular distribution of Hsp90␤, but not Hsp90␣. This is the first example of a co-chaperone with isoform selectivity, and this approach may open novel avenues to understanding the functional differences between Hsp90 isoforms.

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Section: Resultsmentioning

confidence: 99%

“…One of these, GCUNC45 (general cell UNC45), is a co-chaperone that has been implicated in the chaperoning of myosins (12)(13)(14) and of PR 2 (15). In this study, we show that GCUNC45 bound preferentially to the ␤ isoform of Hsp90 in a purified system.…”

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confidence: 99%

GCUNC45 Is the First Hsp90 Co-chaperone to Show α/β Isoform Specificity

Chadli

Felts

Toft

2008

Journal of Biological Chemistry

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“…A new ANG II target identified by SAGE is cardiomyopathy associated 4 (Cmya4) (also known as striated muscle UNC45), which encodes a protein with a role in sarcomere organization (38).…”

Section: Discussionmentioning

confidence: 99%

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

Schwartz¹,

Duka²,

Duka³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Schwartz, Faina, Arvi Duka, Irena Duka, Jing Cui, and Haralambos Gavras. Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression. Am J Physiol Heart Circ Physiol 287: H1957-H1966, 2004. First published July 8, 2004 doi:10.1152/ajpheart.00568.2004.-Although the central role of ANG II in cardiovascular homeostasis is well appreciated, the molecular circuitry of its many actions is not completely understood. With the use of serial analysis of gene expression to assess global transcriptional changes in the heart of mice after continuous 7-day ANG II administration, we identified patterns of gene expression indicative of cardiac remodeling, including coordinate regulation of genes previously described in a context of processes associated with hypertrophy and fibrosis. In addition, we discovered several novel ANG II targets, including characterized genes of known function, recently annotated genes of unknown function, and the putative genes not yet present in current databases. The serial analysis of gene expression approach to assess the role of ANG II presented in this report provides new venues for inquiries into ANG II-mediated cardiac function.genome-wide transcriptional profiling; hypertension; cardiac remodeling; hypertrophy; fibrosis THE KEY ROLE of ANG II in cardiovascular homeostasis is well documented. Although initially known for its vasoconstrictive action, the adverse effects of ANG II elevation on the heart independent of its hemodynamic influence were recognized in the early 1970s (7, 16), and the cardioprotective outcomes of the pharmacological interventions that either prevent the ANG II formation from the inactive angiotensinogen precursor (14) or inhibit its interaction with specific receptors (15, 48) are now well appreciated in clinical practice (6,13,17).Experimental animal studies have shown that ANG II administration can cause multifocal myocardial lesions (16, 47), and, via ANG II type 1 receptors, directly induce cardiac remodeling that involves myocyte hypertrophy (9, 25), fibroblast proliferation, and subsequent fibrosis (47), thus leading to the development of pathological cardiac hypertrophy and, ultimately, heart failure. Both in vivo and in vitro studies revealed that the ANG II effects in the heart are accompanied by changes in gene expression in the cardiac myocytes, fibroblasts, and endothelial cells (24). While the queries of selected ANG II targets supplied important information on several molecular pathways underlying the physiological and pathophysiological actions of ANG II, an all-inclusive view is provided by the genome-wide transcriptional profiling that offers an opportunity to connect separate pieces of the puzzle through the identification of the new players not intuitively obvious from our present understanding of physiology. Thus simultaneous evaluation of 4,000 genes by the use of microarray technology to query the quantitative changes in left ventricular RNA in response to ANG II-induced progression, and, subsequently, regre...

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“…Unc45 is a myosin heavy chain-specific chaperone that was first described in the nematode Caenhorabditis elegans (6). Mammals have two Unc45 genes, encoding two distinct isoforms of the chaperone called Unc45a and Unc45b (7). Unc45b is specifically expressed in striated muscle and acts as the chaperone for cardiac and skeletal muscle myosins.…”

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confidence: 99%

Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells

Kwartler

Chen

Thakur

et al. 2014

Journal of Biological Chemistry

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Background: Genomic duplications involving the smooth muscle myosin heavy chain gene, MYH11, are associated with increased risk for acute aortic dissections. Results: MYH11 overexpression causes increased turnover of contractile proteins through increased autophagy. Conclusion: MYH11 duplications may predispose to aortic disease through increased turnover of contractile proteins and disruption of contractile signaling. Significance: Increased protein turnover may be an important mechanism by which genomic duplications cause human disease.

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Two mammalian UNC-45 isoforms are related to distinct cytoskeletal and muscle-specific functions

Cited by 132 publications

References 55 publications

GCUNC45 Is the First Hsp90 Co-chaperone to Show α/β Isoform Specificity

GCUNC45 Is the First Hsp90 Co-chaperone to Show α/β Isoform Specificity

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells

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