Date Published:
2015 Dec 25
Publication Type:
Journal Article
Authors:
Secondary:
J Biol Chem
Volume:
290
Pagination:
30931-46
Issue:
52
PMID:
26534959
URL:
https://pubmed.ncbi.nlm.nih.gov/26534959
Keywords:
Animals;Brain;Exons;External;Gene Expression Regulation, Enzymologic;HEK293 Cells;HIV Infections;HIV-1;Humans;Mice;Neurons;Nuclear Proteins;Protein-Serine-Threonine Kinases;Protein-Tyrosine Kinases;Ribonucleoproteins;Serine-Arginine Splicing Factors;tat Gene Products, Human Immunodeficiency Virus;tau Proteins;Up-Regulation
Abstract:
<p>The HIV-1 transactivator protein Tat is implicated in the neuronal damage that contributes to neurocognitive impairment affecting people living with HIV/AIDS. Aberrant splicing of TAU exon 10 results in tauopathies characterized by alterations in the proportion of TAU isoforms containing three (3R) or four (4R) microtubule-binding repeats. The splicing factor SC35/SRSF2 binds to nuclear RNA and facilitates the incorporation of exon 10 in the TAU molecule. Here, we utilized clinical samples, an animal model, and neuronal cell cultures and found that Tat promotes TAU 3R up-regulation through increased levels of phosphorylated SC35, which is retained in nuclear speckles. This mechanism involved Tat-mediated increased expression of DYRK1A and was prevented by DYRK1A silencing. In addition, we found that Tat associates with TAU RNA, further demonstrating that Tat interferes with host RNA metabolism in the absence of viral infection. Altogether, our data unravel a novel mechanism of Tat-mediated neuronal toxicity through dysregulation of the SC35-dependent alternative splicing of TAU exon 10. Furthermore, the increased immunostaining of DYRK1A in HIV+ brains without pathology points at dysregulation of DYRK1A as an early event in the neuronal complications of HIV infection.</p>