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Mostoslavsky, Raul

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Mostoslavsky

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Raul

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Mostoslavsky, Raul
Author's Publications: search.filters.isAuthorOfPublication.f10377d9-8791-4b3a-bef0-56bc29af7954

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Now showing 1 - 10 of 11
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    A Unique Subset of Glycolytic Tumour-Propagating Cells Drives Squamous Cell Carcinoma
    (Springer Science and Business Media LLC, 2021-02-22) Choi, Jeeeun; Sebastian, Carlos; Ferrer, Christina M.; Lewis, Caroline A.; Sade-Feldman, Moshe; LaSalle, Thomas; Gonye, Anna; Gimenez-Cassina Lopez, Begona; Abdelmoula, Walid M.; Regan, Michael S.; Cetinbas, Murat; Pascual, Gloria; Wojtkiewicz, Gregory; Silveira, Giorgia G.; Boon, Ruben; Ross, Kenneth; Tirosh, Itay; Saladi, Srinivas V.; Ellisen, Leif; Sadreyev, Ruslan; Benitah, Salvador Aznar; Agar, Nathalie; Hacohen, Nir; Mostoslavsky, Raul
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    SIRT6-dependent cysteine monoubiquitination in the PRE-SET domain of Suv39h1 regulates the NF-κB pathway
    (Nature Publishing Group UK, 2018) Santos-Barriopedro, Irene; Bosch-Presegué, Laia; Marazuela-Duque, Anna; de la Torre, Carolina; Colomer, Carlota; Vazquez, Berta N.; Fuhrmann, Thomas; Martínez-Pastor, Bárbara; Lu, Wenfu; Braun, Thomas; Bober, Eva; Jenuwein, Thomas; Serrano, Lourdes; Esteller, Manel; Chen, Zhenbang; Barceló-Batllori, Silvia; Mostoslavsky, Raul; Espinosa, Lluis; Vaquero, Alejandro
    Sirtuins are NAD+-dependent deacetylases that facilitate cellular stress response. They include SirT6, which protects genome stability and regulates metabolic homeostasis through gene silencing, and whose loss induces an accelerated aging phenotype directly linked to hyperactivation of the NF-κB pathway. Here we show that SirT6 binds to the H3K9me3-specific histone methyltransferase Suv39h1 and induces monoubiquitination of conserved cysteines in the PRE-SET domain of Suv39h1. Following activation of NF-κB signaling Suv39h1 is released from the IκBα locus, subsequently repressing the NF-κB pathway. We propose that SirT6 attenuates the NF-κB pathway through IκBα upregulation via cysteine monoubiquitination and chromatin eviction of Suv39h1. We suggest a mechanism based on SirT6-mediated enhancement of a negative feedback loop that restricts the NF-κB pathway.
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    SIRT6 Is Required for Normal Retinal Function
    (Public Library of Science, 2014) Silberman, Dafne M.; Ross, Kenneth; Sande, Pablo H.; Kubota, Shunsuke; Ramaswamy, Sridhar; Apte, Rajendra S.; Mostoslavsky, Raul
    The retina is one of the major energy consuming tissues within the body. In this context, synaptic transmission between light-excited rod and cone photoreceptors and downstream ON-bipolar neurons is a highly demanding energy consuming process. Sirtuin 6 (SIRT6), a NAD-dependent deacylase, plays a key role in regulating glucose metabolism. In this study, we demonstrate that SIRT6 is highly expressed in the retina, controlling levels of histone H3K9 and H3K56 acetylation. Notably, despite apparent normal histology, SIRT6 deficiency caused major retinal transmission defects concomitant to changes in expression of glycolytic genes and glutamate receptors, as well as elevated levels of apoptosis in inner retina cells. Our results identify SIRT6 as a critical modulator of retinal function, likely through its effects on chromatin.
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    Sirt6 regulates TNFα secretion via hydrolysis of long chain fatty acyl lysine
    (2013) Jiang, Hong; Khan, Saba; Wang, Yi; Charron, Guillaume; He, Bin; Sebastian, Carlos; Du, Jintang; Kim, Ray; Ge, Eva; Mostoslavsky, Raul; Hang, Howard C.; Hao, Quan; Lin, Hening
    The Sir2 family of enzymes or sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases1 and have been implicated in the regulation of transcription, genome stability, metabolism, and lifespan2, 3. However, four of the seven mammalian sirtuins have very weak deacetylase activity in vitro. Here we show that human Sirt6 efficiently removes long chain fatty acyl groups, such as myristoyl, from lysine residues. The crystal structure of Sirt6 reveals a large hydrophobic pocket that can accommodate long chain fatty acyl groups. We demonstrate further that Sirt6 promotes the secretion of tumor necrosis factor α (TNFα) by removing the fatty acyl modification on K19 and K20 of TNFα. Protein lysine fatty acylation has been known to occur in mammalian cells, but the function and regulatory mechanisms of this modification were unknown. Our data suggest that protein lysine fatty acylation is a novel mechanism that regulates protein secretion. The discovery of Sirt6 as an enzyme that controls protein lysine fatty acylation provides new opportunities to investigate the physiological function of the previously ignored protein posttranslational modification.
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    Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress
    (NLM-Export, 2014) Shaughnessy, Daniel T.; McAllister, Kimberly; Worth, Leroy; Haugen, Astrid C.; Meyer, Joel N.; Domann, Frederick E.; Van Houten, Bennett; Mostoslavsky, Raul; Bultman, Scott J.; Baccarelli, Andrea; Begley, Thomas J.; Sobol, Robert W.; Hirschey, Matthew D.; Ideker, Trey; Santos, Janine H.; Copeland, William C.; Tice, Raymond R.; Balshaw, David M.; Tyson, Frederick L.
    Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria–nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. Objectives: We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function. Methods: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25–26 March 2013. Here, we summarize key points and ideas emerging from this meeting. Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways. Conclusions: Understanding mitochondria–cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors. Citation: Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, Van Houten B, Mostoslavsky R, Bultman SJ, Baccarelli AA, Begley TJ, Sobol RW, Hirschey MD, Ideker T, Santos JH, Copeland WC, Tice RR, Balshaw DM, Tyson FL. 2014. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect 122:1271–1278; http://dx.doi.org/10.1289/ehp.1408418
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    Sox2 Suppresses Gastric Tumorigenesis in Mice
    (Elsevier BV, 2016-08-16) Sarkar, Abby; Huebner, Aaron; Sulahian, Rita; Anselmo, Anthony; Xu, Xinsen; Flattery, Kyle; Desai, Niyati; Sebastian, Carlos; Yram, Mary Anna; Arnold, Katrin; Rivera, Miguel; Mostoslavsky, Raul; Bronson, Roderick; Bass, Adam; Sadreyev, Ruslan; Shivdasani, Ramesh; Hochedlinger, Konrad
    Sox2 expression marks gastric stem and progenitor cells, raising important questions regarding the genes regulated by Sox2 and the role of Sox2 itself during stomach homeostasis and disease. By using ChIP-seq analysis, we have found that the majority of Sox2 targets in gastric epithelial cells are tissue specific and related to functions such as endoderm development, Wnt signaling, and gastric cancer. Unexpectedly, we found that Sox2 itself is dispensable for gastric stem cell and epithelial self-renewal, yet Sox2(+) cells are highly susceptible to tumorigenesis in an Apc/Wnt-driven mouse model. Moreover, Sox2 loss enhances, rather than impairs, tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, providing a mechanistic basis for the observed phenotype. Together, these data identify Sox2 as a context-dependent tumor suppressor protein that is dispensable for normal tissue regeneration but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes.
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    Sirt6 regulates dendritic cell differentiation, maturation, and function
    (Impact Journals LLC, 2016) Lasigliè, Denise; Boero, Silvia; Bauer, Inga; Morando, Sara; Damonte, Patrizia; Cea, Michele; Monacelli, Fiammetta; Odetti, Paizio; Ballestrero, Alberto; Uccelli, Antonio; Mostoslavsky, Raul; Poggi, Alessandro; Nencioni, Alessio
    Dendritic cells (DCs) are antigen-presenting cells that critically influence decisions about immune activation or tolerance. Impaired DC function is at the core of common chronic disorders and contributes to reduce immunocompetence during aging. Knowledge on the mechanisms regulating DC generation and function is necessary to understand the immune system and to prevent disease and immunosenescence. Here we show that the sirtuin Sirt6, which was previously linked to healthspan promotion, stimulates the development of myeloid, conventional DCs (cDCs). Sirt6-knockout (Sirt6KO) mice exhibit low frequencies of bone marrow cDC precursors and low yields of bone marrow-derived cDCs compared to wild-type (WT) animals. Sirt6KO cDCs express lower levels of class II MHC, of costimulatory molecules, and of the chemokine receptor CCR7, and are less immunostimulatory compared to WT cDCs. Similar effects in terms of differentiation and immunostimulatory capacity were observed in human monocyte-derived DCs in response to SIRT6 inhibition. Finally, while Sirt6KO cDCs show an overall reduction in their ability to produce IL-12, TNF-α and IL-6 secretion varies dependent on the stimulus, being reduced in response to CpG, but increased in response to other Toll-like receptor ligands. In conclusion, Sirt6 plays a crucial role in cDC differentiation and function and reduced Sirt6 activity may contribute to immunosenescence.
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    SIRT1 Activators: The Evidence STACks up
    (Impact Journals LLC, 2013) Kugel, Sita; Mostoslavsky, Raul
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    Sirtuins, Metabolism, and Cancer
    (Frontiers Research Foundation, 2012) Martinez-Pastor, Barbara; Mostoslavsky, Raul
    More than a decade ago, sirtuins were discovered as a highly conserved family of NAD+-dependent enzymes that extend lifespan in lower organisms. In mammals, sirtuins are key regulators of stress responses and metabolism, influencing a range of diseases, including diabetes, neurodegeneration, and cancer. In recent years, new functions of sirtuins have been characterized, uncovering the underlying mechanisms of their multifaceted role in metabolism. Here, we specifically review recent progress on the role of sirtuins in DNA repair and energy metabolism, further discussing the implication of sirtuins in the biology of cancer.
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    The histone deacetylase SIRT6, a critical modulator of metabolism and tumorigenesis
    (BioMed Central, 2012) Sebastian, Carlos; Zhong, Lei; Silberman, Magali; Toiber, Deborah; Martinez, Barbara; Etchegaray, Jean-Pierre; Cosentino, Claudia; Giacosa, Sofia; Mostoslavsky, Raul