Thioredoxin reductase-1 negatively regulates HIV-1 transactivating protein Tat-dependent transcription in human macrophages

Parisa Kalantari, Vivek Narayan, Sathish K Natarajan, Kambadur Muralidhar, Ujjawal H. Gandhi, Hema Vunta, Andrew J. Henderson, K. Sandeep Prabhu

Research output: Contribution to journalArticle

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Abstract

Epidemiological studies suggest a correlation between severity of acquired immunodeficiency syndrome (AIDS) and selenium deficiency, indicating a protective role for this anti-oxidant during HIV infection. Here we demonstrate that thioredoxin reductase-1 (TR1), a selenium-containing pyridine nucleotide-disulfide oxidoreductase that reduces protein disulfides to free thiols, negatively regulates the activity of the HIV-1 encoded transcriptional activator, Tat, in human macrophages. We used a small interfering RNA approach as well as a high affinity substrate of TR1, ebselen, to demonstrate that Tat-dependent transcription and HIV-1 replication were significantly increased in human macrophages when TR1 activity was reduced. The increase in HIV-1 replication in TR1 small interfering RNA-treated cells was independent of the redox-sensitive transcription factor, NF-κB. These studies indicate that TR-1 acts as a negative regulator of Tat-dependent transcription. Furthermore, in vitro biochemical assays with recombinant Tat protein confirmed that TR1 targets two disulfide bonds within the Cys-rich motif required for efficient HIV-1 transactivation. Increasing TR1 expression along with other selenoproteins by supplementing with selenium suggests a potential inexpensive adjuvant therapy for HIV/AIDS patients.

Original languageEnglish (US)
Pages (from-to)33183-33190
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number48
DOIs
StatePublished - Nov 28 2008

Fingerprint

Thioredoxin Reductase 1
tat Gene Products
Macrophages
Transcription
HIV-1
Selenium
Disulfides
Small Interfering RNA
Acquired Immunodeficiency Syndrome
Selenoproteins
Recombinant proteins
Recombinant Proteins
Sulfhydryl Compounds
Oxidants
Transcriptional Activation
Oxidation-Reduction
HIV Infections
Epidemiologic Studies
Assays
Oxidoreductases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Thioredoxin reductase-1 negatively regulates HIV-1 transactivating protein Tat-dependent transcription in human macrophages. / Kalantari, Parisa; Narayan, Vivek; Natarajan, Sathish K; Muralidhar, Kambadur; Gandhi, Ujjawal H.; Vunta, Hema; Henderson, Andrew J.; Prabhu, K. Sandeep.

In: Journal of Biological Chemistry, Vol. 283, No. 48, 28.11.2008, p. 33183-33190.

Research output: Contribution to journalArticle

Kalantari, Parisa ; Narayan, Vivek ; Natarajan, Sathish K ; Muralidhar, Kambadur ; Gandhi, Ujjawal H. ; Vunta, Hema ; Henderson, Andrew J. ; Prabhu, K. Sandeep. / Thioredoxin reductase-1 negatively regulates HIV-1 transactivating protein Tat-dependent transcription in human macrophages. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 48. pp. 33183-33190.
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