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Santerre M , Bagashev A , Gorecki L , Lysek KZ , Wang Y , Shrestha J , Carpio-Cano FD , Mukerjee R , Sawaya BE
HIV-1 Tat protein promotes neuronal dysregulation by inhibiting E2F transcription factor 3 (E2F3)
J Biol Chem. 2019 Mar 8;294(10) :3618-3633
PMID: 30591585    PMCID: PMC6416426    URL: https://www.ncbi.nlm.nih.gov/pubmed/30591585
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Abstract
Individuals who are infected with HIV-1 accumulate damage to cells and tissues (e.g. neurons) that are not directly infected by the virus. These include changes known as HIV-associated neurodegenerative disorder (HAND), leading to the loss of neuronal functions, including synaptic long-term potentiation (LTP). Several mechanisms have been proposed for HAND, including direct effects of viral proteins such as the Tat protein. Searching for the mechanisms involved, we found here that HIV-1 Tat inhibits E2F transcription factor 3 (E2F3), CAMP-responsive element-binding protein (CREB), and brain-derived neurotropic factor (BDNF) by up-regulating the microRNA miR-34a. These changes rendered murine neurons dysfunctional by promoting neurite retraction, and we also demonstrate that E2F3 is a specific target of miR-34a. Interestingly, bioinformatics analysis revealed the presence of an E2F3-binding site within the CREB promoter, which we validated with ChIP and transient transfection assays. Of note, luciferase reporter assays revealed that E2F3 up-regulates CREB expression and that Tat interferes with this up-regulation. Further, we show that miR-34a inhibition or E2F3 overexpression neutralizes Tat's effects and restores normal distribution of the synaptic protein synaptophysin, confirming that Tat alters these factors, leading to neurite retraction inhibition. Our results suggest that E2F3 is a key player in neuronal functions and may represent a good target for preventing the development of HAND.
Notes
Export Date: 1 May 2019 R01 AG054411/AG/NIA NIH HHS/ R01 MH093331/MH/NIMH NIH HHS/ R01 NS059327/NS/NINDS NIH HHS/ R01 NS076402/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural J Biol Chem. 2019 Mar 8;294(10):3618-3633. doi: 10.1074/jbc.RA118.003744. Epub 2018 Dec 27.