Nitration of Hsp90 on Tyrosine 33 Regulates Mitochondrial Metabolism

Franco, María Clara; Ricart, Karina; González, Analía Silvia; Dennys, Cassandra N.; Nelson, Pascal A.; Janes, Michael; Mehl, Ryan A.; Landar, Aimee; Estévez, Álvaro G.

doi:10.1074/jbc.m115.663278

Cited by 36 publications

(44 citation statements)

References 54 publications

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“…This is illustrated by the demonstration that nitration of a single tyrosine residue in HSP90 is sufficient to convert HSP90 from a pro-survival protein into a mediator of motor neuron death [ 74 ]. Nitration of the HSP90 at position 33 induces conformational changes and its translocation to the mitochondrial outer membrane, in which it probably interacts with one or more mitochondrial proteins and thereby altering mitochondrial activity, a sequence of events that may be associated with pro-survival mechanisms in cancer cells [ 75 ].…”

Section: Discussionmentioning

confidence: 99%

The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells

et al. 2015

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HSP60 undergoes changes in quantity and distribution in some types of tumors suggesting a participation of the chaperonin in the mechanism of transformation and cancer progression. Suberoylanilide hydroxamic acid (SAHA), a member of a family of histone deacetylase inhibitors (HDACi), has anti-cancer potential but its interaction, if any, with HSP60 has not been elucidated. We investigated the effects of SAHA in a human lung-derived carcinoma cell line (H292). We analysed cell viability and cycle; oxidative stress markers; mitochondrial integrity; HSP60 protein and mRNA levels; and HSP60 post-translational modifications, and its secretion. We found that SAHA is cytotoxic for H292 cells, interrupting the cycle at the G2/M phase, which is followed by death; cytotoxicity is associated with oxidative stress, mitochondrial damage, and diminution of intracellular levels of HSP60; HSP60 undergoes a post-translational modification and becomes nitrated; and nitrated HSP60 is exported via exosomes. We propose that SAHA causes ROS overproduction and mitochondrial dysfunction, which leads to HSP60 nitration and release into the intercellular space and circulation to interact with the immune system. These successive steps might constitute the mechanism of the anti-tumor action of SAHA and provide a basis to design supplementary therapeutic strategies targeting HSP60, which would be more efficacious than the compound alone.

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Section: Discussionmentioning

confidence: 99%

The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells

et al. 2015

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“…Peroxynitrite can move across cell membranes through either anion channels (anionic form) or passive diffusion (protonated forms) and can induce toxicity approximately 10 μm from its site of formation [116]. Hence, in addition to the direct effect on astrocyte biology [112], the production of peroxynitrite by astrocytes can induce oxidative and nitrative stress in motor neurons, affecting mitochondrial function and inducing cell death [113, 115, 117–120]. Thus, oxidative stress and mitochondrial dysfunction in ALS astrocytes have the potential to induce motor neuron death and/or contribute to propagate the disease.…”

Section: Pathways Involved In Astrocyte-mediated Motor Neuron Toximentioning

confidence: 99%

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Pehar

Harlan

Killoy

et al. 2018

CPD

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.

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“…As with all Ox-PTMs, it is difficult to establish direct and quantitative relationships between extent of nitration on specific proteins and biological responses in cells and the influence of protein tyrosine nitration is often obscured by the multiplicity of oxidative modifications. GCE has already begun to untangle some of this complexity [ 78 – 81 ].…”

Section: Ox-ptms Of Aromatic Residuesmentioning

confidence: 99%

Genetic Code Expansion: A Powerful Tool for Understanding the Physiological Consequences of Oxidative Stress Protein Modifications

Porter

Mehl

2018

Oxidative Medicine and Cellular Longevity

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Posttranslational modifications resulting from oxidation of proteins (Ox-PTMs) are present intracellularly under conditions of oxidative stress as well as basal conditions. In the past, these modifications were thought to be generic protein damage, but it has become increasingly clear that Ox-PTMs can have specific physiological effects. It is an arduous task to distinguish between the two cases, as multiple Ox-PTMs occur simultaneously on the same protein, convoluting analysis. Genetic code expansion (GCE) has emerged as a powerful tool to overcome this challenge as it allows for the site-specific incorporation of an Ox-PTM into translated protein. The resulting homogeneously modified protein products can then be rigorously characterized for the effects of individual Ox-PTMs. We outline the strengths and weaknesses of GCE as they relate to the field of oxidative stress and Ox-PTMs. An overview of the Ox-PTMs that have been genetically encoded and applications of GCE to the study of Ox-PTMs, including antibody validation and therapeutic development, is described.

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Nitration of Hsp90 on Tyrosine 33 Regulates Mitochondrial Metabolism

Cited by 36 publications

References 54 publications

The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells

The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Genetic Code Expansion: A Powerful Tool for Understanding the Physiological Consequences of Oxidative Stress Protein Modifications

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