Human Immunodeficiency Virus Type 1 Tat Protein Inhibits the SIRT1 Deacetylase and Induces T Cell Hyperactivation

Kwon, Hye Sook; Brent, Michael; Getachew, Ruth; Jayakumar, Prerana; Chen, Lin Feng; Schnölzer, Martina; McBurney, Michael W.; Marmorstein, Ronen; Greene, Warner C.; Ott, Melanie

doi:10.1016/j.chom.2008.02.002

Cited by 155 publications

(177 citation statements)

References 64 publications

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“…4D). Previous studies have shown that the viral transactivator Tat from HIV-1 can inhibit SIRT1 through binding to the SIRT1 deacetylase domain (46). Interestingly, cyclin T1 is an essential cofactor in Tat-mediated viral transcription, and its acetylation leads to the formation of an active form of the PTEFb complex and initiation of viral transcription (47).…”

Section: Fig 3 Enrichment and Clustering Analysis Of Kac Substratementioning

confidence: 99%

Quantitative Acetylome Analysis Reveals the Roles of SIRT1 in Regulating Diverse Substrates and Cellular Pathways

Chen

Zhao

Yang

et al. 2012

Molecular & Cellular Proteomics

193

159

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Despite of the progress in identifying many Lysine (Lys)1 acetylation is a dynamic, reversible, and evolutionarily conserved protein post-translational modification (PTM). After the discovery of Lys acetylation in histones more than forty years ago (1), early studies mainly focused on histones and transcription factors, establishing the modification's fundamental role in DNA-templated biological processes (2, 3). The discovery of Lys acetylation in tubulin and the presence of sirtuins in mitochondria argued that Lys acetylation may not be restricted to nuclei (4 -6). The complexity of Lys acetylomes outside the nuclei and the high abundance of the PTM in mitochondria revealed by proteomics studies suggested that the regulatory functions of this PTM may mirror those of protein phosphorylation (7-9).Lys acetylation is regulated by two groups of enzymes with opposing activities, lysine acetyltransferases and deacetylases (10). Sirtuins are a family of highly conserved NAD ϩ -dependent deacetylases (11,12). Numerous studies, mainly focusing on the family's founding member, SIRT1 in mammals or Sir2, the enzyme's homolog in yeast, show that sirtuins regulate diverse cellular functions and appear to affect a variety of aging-related diseases, such as cancer, metabolic diseases, and inflammation and are involved in pathways such as metabolisms, oxidative stress, DNA damage, cell cycle, and signaling (12-15). A number of protein substrates for SIRT1 have been identified including p53, DNA methyltransferase 1 (DNMT1), NF-B, forkhead transcription factors, PGC-1␣, and histones (16 -22). Despite significant progress in the past decade, the molecular mechanisms by which SIRT1 regulates cellular physiology are not well understood. A major hurdle in our understanding of SIRT1 biology is our incomplete knowledge of Lys acetylation proteins that mediate SIRT1 functions. Because SIRT1 is a lysine deacetylase, a major mechanism for SIRT1 to exert its functions should be its deacetylation activity. However, SIRT1-induced lysine acetylation proteins are far from complete. This knowledge limitation also exists with other deacetylases as well as with lysine acetyltransferases, representing a major challenge in Lys acetylation biology and in evaluating clinical compounds that target dysregulated Lysacetylation regulatory enzymes.Here we report the first proteomics quantification of Lys acetylation in response to a regulatory enzyme. Our study identified 4623 Lys acetylation sites from SIRT1 ϩ/ϩ and SIRT1 Ϫ/Ϫ MEF cells, among which 4130 Lys acetylation sites were quantified. The data identified multiple pathways that are affected by SIRT1. From this wealth of new information on the SIRT1-modulated Lys acetylome, we discovered consensus motifs for SIRT1-mediated Lys acetylation sites and identified extensive correlation between Lys acetylation and phosphorylation, SUMOylation, and mutations associated with disease,

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Section: Fig 3 Enrichment and Clustering Analysis Of Kac Substratementioning

confidence: 99%

Quantitative Acetylome Analysis Reveals the Roles of SIRT1 in Regulating Diverse Substrates and Cellular Pathways

Chen

Zhao

Yang

et al. 2012

Molecular & Cellular Proteomics

193

159

View full text Add to dashboard Cite

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“…Kwon and coworkers have recently confirmed and expanded these results, by showing that this pathway is targeted and exploited by the HIV virus. The authors wished to understand the mechanism by which the HIV transcriptional activator Tat can positively regulate NFkB activity and induce IL-2 expression in infected lymphocytes [17]. In their work, they elegantly demonstrate that Tat inhibits SIRT1 enzymatic activity by binding to its acetyl-lysine-binding domain.…”

Section: Sirt1 Negatively Regulates Nfkb Activitymentioning

confidence: 99%

Sirtuins and inflammation: Friends or foes?

Gallí

Gool

Léo

2011

Biochemical Pharmacology

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Lysine acetylation/deacetylation has been recognized as an important posttranslational modification regulating numerous cellular processes. Sirtuins represent novel players in these complex regulatory circuits. These NAD-dependent lysine-deacetylases have attracted much interest based on their role in the regulation of lifespan in lower organisms, and their capacity to interfere with cell growth, proliferation and survival in response to stress. Their absolute requirement for NAD suggests that these enzymes may represent an important molecular link between metabolism and several human disorders such as diabetes and cancer. More recently, the identification of several transcription factors known to play a role in the immune system as sirtuin substrates has suggested that this family of enzymes may also play an important role in the regulation of inflammation, a pathological situation with clear links to metabolism and ageing in humans. We review herein the possible links between nuclear sirtuins and the regulation of an immune response, and discuss the possible strategies that may lead to the development of novel therapeutic approaches to treat inflammation by targeting sirtuin activity.

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“…CD4, MHC-I/II, CD25, and CD28), and modifies autophagic flux. Tat has pleiotropic effects on cellular gene expression, metabolism, and signal cascades [22] that can cause T-cell hyperactivation [23] and neurotoxicity. In viral latency (Table 2), the paucity of viral protein expression appears chiefly to result from the infection of activated CD4 1 cells that later return to a resting state.…”

Section: Sequence Diversitymentioning

confidence: 99%

HIV/AIDS: 30 Years of progress and future challenges

Killian

Levy

2011

Eur J Immunol

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Acquired immune deficiency syndrome (AIDS) was first described 30 years ago in a report from the US Centers for Disease Control. Two years later the causative virus was identified and afterwards named the human immunodeficiency virus (HIV). This article reviews the progress made in the three decades since the recognition of AIDS and the discovery of HIV, with respect to the virus, the infected cell, and the host, as well as directions for future studies.

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Human Immunodeficiency Virus Type 1 Tat Protein Inhibits the SIRT1 Deacetylase and Induces T Cell Hyperactivation

Cited by 155 publications

References 64 publications

Quantitative Acetylome Analysis Reveals the Roles of SIRT1 in Regulating Diverse Substrates and Cellular Pathways

Quantitative Acetylome Analysis Reveals the Roles of SIRT1 in Regulating Diverse Substrates and Cellular Pathways

Sirtuins and inflammation: Friends or foes?

HIV/AIDS: 30 Years of progress and future challenges

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