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

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

doi:10.1016/j.chom.2008.02.002

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

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

Research output: Contribution to journal › Article › peer-review

Abstract

Symptoms of T cell hyperactivation shape the course and outcome of HIV-1 infection, but the mechanism(s) underlying this chronic immune activation are not well understood. We find that the viral transactivator Tat promotes hyperactivation of T cells by blocking the nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase SIRT1. Tat directly interacts with the deacetylase domain of SIRT1 and blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit of NF-κB. Because acetylated p65 is more active as a transcription factor, Tat hyperactivates the expression of NF-κB-responsive genes, a function lost in SIRT1-/- cells. These results support a model where the normal function of SIRT1 as a negative regulator of T cell activation is suppressed by Tat during HIV infection. These events likely contribute to the state of immune cell hyperactivation found in HIV-infected individuals.

Original language	English (US)
Pages (from-to)	158-167
Number of pages	10
Journal	Cell Host and Microbe
Volume	3
Issue number	3
DOIs	https://doi.org/10.1016/j.chom.2008.02.002
State	Published - Mar 13 2008
Externally published	Yes

Keywords

MICROBIO
SIGNALING

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

Online availability

10.1016/j.chom.2008.02.002

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

abstract = "Symptoms of T cell hyperactivation shape the course and outcome of HIV-1 infection, but the mechanism(s) underlying this chronic immune activation are not well understood. We find that the viral transactivator Tat promotes hyperactivation of T cells by blocking the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase SIRT1. Tat directly interacts with the deacetylase domain of SIRT1 and blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit of NF-κB. Because acetylated p65 is more active as a transcription factor, Tat hyperactivates the expression of NF-κB-responsive genes, a function lost in SIRT1-/- cells. These results support a model where the normal function of SIRT1 as a negative regulator of T cell activation is suppressed by Tat during HIV infection. These events likely contribute to the state of immune cell hyperactivation found in HIV-infected individuals.",

keywords = "MICROBIO, SIGNALING",

author = "Kwon, {Hye Sook} and Brent, {Michael M.} and Ruth Getachew and Prerana Jayakumar and Chen, {Lin Feng} and Martina Schnolzer and McBurney, {Michael W.} and Ronen Marmorstein and Greene, {Warner C.} and Melanie Ott",

note = "Funding Information: We thank Vittorio Sartorelli, Narendra Chirmule, Keith Yamamoto, David Sinclair, and Jordan Pober for sharing their reagents; Angelika Pedal and Thomas Conrad for technical assistance; Brandi Sanders and Eric Verdin for helpful discussions; John Carroll and Alisha Wilson for graphics; Gary Howard for editing the manuscript; and Veronica Fonseca for administrative assistance. H.-S.K. is supported by a fellowship from the University-wide AIDS Research Program (UARP), L.-F.C. by an investigator award from the Arthritis Foundation, and M.O. by grants from the Gladstone Institute, the NIH (1R56AI067118-01A2), and the UARP (ID07-GI103). ",

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month = mar,

day = "13",

doi = "10.1016/j.chom.2008.02.002",

language = "English (US)",

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journal = "Cell Host and Microbe",

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T1 - Human Immunodeficiency Virus Type 1 Tat Protein Inhibits the SIRT1 Deacetylase and Induces T Cell Hyperactivation

AU - Kwon, Hye Sook

AU - Brent, Michael M.

AU - Getachew, Ruth

AU - Jayakumar, Prerana

AU - Chen, Lin Feng

AU - Schnolzer, Martina

AU - McBurney, Michael W.

AU - Marmorstein, Ronen

AU - Greene, Warner C.

AU - Ott, Melanie

N1 - Funding Information: We thank Vittorio Sartorelli, Narendra Chirmule, Keith Yamamoto, David Sinclair, and Jordan Pober for sharing their reagents; Angelika Pedal and Thomas Conrad for technical assistance; Brandi Sanders and Eric Verdin for helpful discussions; John Carroll and Alisha Wilson for graphics; Gary Howard for editing the manuscript; and Veronica Fonseca for administrative assistance. H.-S.K. is supported by a fellowship from the University-wide AIDS Research Program (UARP), L.-F.C. by an investigator award from the Arthritis Foundation, and M.O. by grants from the Gladstone Institute, the NIH (1R56AI067118-01A2), and the UARP (ID07-GI103).

PY - 2008/3/13

Y1 - 2008/3/13

N2 - Symptoms of T cell hyperactivation shape the course and outcome of HIV-1 infection, but the mechanism(s) underlying this chronic immune activation are not well understood. We find that the viral transactivator Tat promotes hyperactivation of T cells by blocking the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase SIRT1. Tat directly interacts with the deacetylase domain of SIRT1 and blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit of NF-κB. Because acetylated p65 is more active as a transcription factor, Tat hyperactivates the expression of NF-κB-responsive genes, a function lost in SIRT1-/- cells. These results support a model where the normal function of SIRT1 as a negative regulator of T cell activation is suppressed by Tat during HIV infection. These events likely contribute to the state of immune cell hyperactivation found in HIV-infected individuals.

AB - Symptoms of T cell hyperactivation shape the course and outcome of HIV-1 infection, but the mechanism(s) underlying this chronic immune activation are not well understood. We find that the viral transactivator Tat promotes hyperactivation of T cells by blocking the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase SIRT1. Tat directly interacts with the deacetylase domain of SIRT1 and blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit of NF-κB. Because acetylated p65 is more active as a transcription factor, Tat hyperactivates the expression of NF-κB-responsive genes, a function lost in SIRT1-/- cells. These results support a model where the normal function of SIRT1 as a negative regulator of T cell activation is suppressed by Tat during HIV infection. These events likely contribute to the state of immune cell hyperactivation found in HIV-infected individuals.

KW - MICROBIO

KW - SIGNALING

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

Abstract

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