Hsp90, the Concertmaster: Tuning Transcription

Khurana, Nidhi; Bhattacharyya, Sunanda

doi:10.3389/fonc.2015.00100

Cited by 56 publications

(31 citation statements)

References 66 publications

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“…As HSP90 chaperoning mechanisms can be altered in cancer cells (40) and therefore in cell lines, the role of HSP90 in MeV replication was also assessed in a more relevant system based on MeV infection of primary slices of murine hippocampus conserving the three-dimensional architecture of the brain (30). HSP90 activity was also found to be critical in an ex vivo model of MeV infection of the mouse brain ( Fig.…”

Section: Hsp90 Activity Is Required For Mev Growth At a Postentry Stepmentioning

confidence: 99%

“…HSP90 belongs to the essential cellular proteins, since several hundred client proteins, including major cellular kinases, rely on its chaperon activity (40)(41)(42). The involvement of HSP90 activity in an intracellular process is best studied with geldanamycin and its derivatives that compete with ATP for binding to HSP90's ATPase site (43).…”

Section: Hsp90 Activity Is Required For Mev Growth At a Postentry Stepmentioning

confidence: 99%

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HSP90 Chaperoning in Addition to Phosphoprotein Required for Folding but Not for Supporting Enzymatic Activities of Measles and Nipah Virus L Polymerases

Bloyet

Welsch

Enchéry

et al. 2016

J Virol

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Nonsegmented negative-stranded RNA viruses, or members of the order Mononegavirales, share a conserved gene order and the use of elaborate transcription and replication machinery made up of at least four molecular partners. These partners have coevolved with the acquisition of the permanent encapsidation of the entire genome by the nucleoprotein (N) and the use of this N-RNA complex as a template for the viral polymerase composed of the phosphoprotein (P) and the large enzymatic protein (L). Not only is P required for polymerase function, but it also stabilizes the L protein through an unknown underlying molecular mechanism. By using NVP-AUY922 and/or 17-dimethylaminoethylamino-17-demethoxygeldanamycin as specific inhibitors of cellular heat shock protein 90 (HSP90), we found that efficient chaperoning of L by HSP90 requires P in the measles, Nipah, and vesicular stomatitis viruses. While the production of P remains unchanged in the presence of HSP90 inhibitors, the production of soluble and functional L requires both P and HSP90 activity. Measles virus P can bind the N terminus of L in the absence of HSP90 activity. Both HSP90 and P are required for the folding of L, as evidenced by a luciferase reporter insert fused within measles virus L. HSP90 acts as a true chaperon; its activity is transient and dispensable for the activity of measles and Nipah virus polymerases of virion origin. That the cellular chaperoning of a viral polymerase into a soluble functional enzyme requires the assistance of another viral protein constitutes a new paradigm that seems to be conserved within the Mononegavirales order. IMPORTANCEViruses are obligate intracellular parasites that require a cellular environment for their replication. Some viruses particularly depend on the cellular chaperoning apparatus. We report here that for measles virus, successful chaperoning of the viral L polymerase mediated by heat shock protein 90 (HSP90) requires the presence of the viral phosphoprotein (P). Indeed, while P protein binds to the N terminus of L independently of HSP90 activity, both HSP90 and P are required to produce stable, soluble, folded, and functional L proteins. Once formed, the mature P؉L complex no longer requires HSP90 to exert its polymerase functions. Such a new paradigm for the maturation of a viral polymerase appears to be conserved in several members of the Mononegavirales order, including the Nipah and vesicular stomatitis viruses. Viruses with a nonsegmented negative-stranded RNA genome, or members of the order Mononegavirales, share a common and highly conserved genomic organization and replication machinery that are unique in the living world. Indeed, the L protein, or polymerase, which is endowed with all of the enzymatic activities required for the synthesis of RNA and the capping and polyadenylation of viral transcripts, cannot use naked viral genomic RNA in a processive way (1). Instead, L associates with the phosphoprotein (P) to dynamically anchor the polymerase complex to the nucleocapsid and/or to enable...

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Section: Hsp90 Activity Is Required For Mev Growth At a Postentry Stepmentioning

confidence: 99%

Section: Hsp90 Activity Is Required For Mev Growth At a Postentry Stepmentioning

confidence: 99%

HSP90 Chaperoning in Addition to Phosphoprotein Required for Folding but Not for Supporting Enzymatic Activities of Measles and Nipah Virus L Polymerases

Bloyet

Welsch

Enchéry

et al. 2016

J Virol

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“…Hsps are expressed at high levels in a wide range of tumors and are closely associated with resistance to therapy (3)(4)(5). The chaperone functions of Hsps, especially Hsp90, are often subverted during oncogenesis, allowing mutant proteins to retain or even gain function (1,2,6). Many mutations associated with human disease, in particular cancer, are predicted to affect protein stability (7).…”

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confidence: 99%

Heat shock proteins stimulate APOBEC-3–mediated cytidine deamination in the hepatitis B virus

Chen¹,

Eggerman

Bocharov³

et al. 2017

Journal of Biological Chemistry

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Apolipoprotein B mRNA-editing enzyme catalytic subunit 3 (APOBEC-3) enzymes are cytidine deaminases that are broadly and constitutively expressed. They are often up-regulated during carcinogenesis and candidate genes for causing the major single-base substitution in cancer-associated DNA mutations. Moreover, APOBEC-3s are involved in host innate immunity against many viruses. However, how APOBEC-3 mutational activity is regulated in normal and pathological conditions remains largely unknown. Heat shock protein levels are often elevated in both carcinogenesis and viral infection and are associated with DNA mutations. Here, using mutational analyses of hepatitis B virus (HBV), we found that Hsp90 stimulates deamination activity of APOBEC-3G (A3G), A3B, and A3C during co-expression in human liver HepG2 cells. Hsp90 directly stimulated A3G deamination activity when the purified proteins were used in reactions. Hsp40, -60, and -70 also had variable stimulatory effects in the cellular assay, but not Sequencing analyses further demonstrated that Hsp90 increased both A3G cytosine mutation efficiency on HBV DNA and total HBV mutation frequency. In addition, Hsp90 shifted A3G's cytosine region selection in HBV DNA and increased A3G's 5' nucleoside preference for deoxycytidine (5'-CC). Furthermore, the Hsp90 inhibitor 17--allylamino-17-demethoxygeldanamycin dose dependently inhibited A3G and A3B mutational activity on HBV viral DNA. Hsp90 knockdown by siRNA or by Hsp90 active-site mutation also decreased A3G activity. These results indicate that heat shock proteins, in particular Hsp90, stimulate APOBEC-3-mediated DNA deamination activity, suggesting a potential physiological role in carcinogenesis and viral innate immunity.

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“…Hsp90β (Hsp90AB1) is regarded as a constitutive expression while Hsp90α (Hsp90AA1) as an inducible expression, it is proved that they have 86% amino acid sequence identity (7). Hsp90 has been found as a critical regulator of cell proliferation, development, mobility and metastasis in malignant tumors, which facilitates maturation and activation of oncogenic proteins, including many kinases and transcription regulatory factors (8). Also, Hsp90 exerts anti-apoptotic activity and affects growth processes tumor cells, and overexpression of Hsp90 has been obviously associated with drug resistance…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism and targeted therapy of Hsp90 involved in lung cancer: New discoveries and developments (Review)

Biaoxue

Yang

2017

Int J Oncol

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The exploration of the molecular mechanisms and signaling pathways on lung cancer is very important for developing new strategies of diagnosis and treatment to this disease, such as finding valuable lung cancer markers and molecularly targeted therapies. Previously, a number of studies disclose that heat shock protein 90 (Hsp90) is upregulated in cancer cells, tissues and serum of lung cancer patients, and its upregulation intimately correlates with the occurrence, development and outcome of lung cancer. On the contrary, inhibition of Hsp90 can suppress cell proliferation, motility and metastasis of lung cancer and promote apoptosis of lung cancer cells via complex signaling pathways. In addition, a series of Hsp90 inhibitors have been investigated as effective molecular targeted therapy tactics fighting against lung cancer. This review, systematically summarizes the role of Hsp90 in lung cancer, the molecular mechanisms and development of anti-Hsp90 treatment in lung cancer.

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Hsp90, the Concertmaster: Tuning Transcription

Cited by 56 publications

References 66 publications

HSP90 Chaperoning in Addition to Phosphoprotein Required for Folding but Not for Supporting Enzymatic Activities of Measles and Nipah Virus L Polymerases

HSP90 Chaperoning in Addition to Phosphoprotein Required for Folding but Not for Supporting Enzymatic Activities of Measles and Nipah Virus L Polymerases

Heat shock proteins stimulate APOBEC-3–mediated cytidine deamination in the hepatitis B virus

Molecular mechanism and targeted therapy of Hsp90 involved in lung cancer: New discoveries and developments (Review)

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