HIV-1-Tat Protein Inhibits SC35-mediated Tau Exon 10 Inclusion through Up-regulation of DYRK1A Kinase.

TitleHIV-1-Tat Protein Inhibits SC35-mediated Tau Exon 10 Inclusion through Up-regulation of DYRK1A Kinase.
Publication TypeJournal Article
Year of Publication2015
AuthorsKadri, F, Pacifici, M, Wilk, A, Parker-Struckhoff, A, Del Valle, L, Hauser, KF, Knapp, PE, Parsons, C, Jeansonne, D, Lassak, A, Peruzzi, F
JournalJ Biol Chem
Volume290
Issue52
Pagination30931-46
Date Published2015 Dec 25
ISSN1083-351X
KeywordsAnimals, Brain, Exons, 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

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.

DOI10.1074/jbc.M115.675751
Alternate JournalJ Biol Chem
PubMed ID26534959
PubMed Central IDPMC4692221
Grant ListK02 DA027374 / DA / NIDA NIH HHS / United States
1U54 GM104940 / GM / NIGMS NIH HHS / United States
U54 GM104940 / GM / NIGMS NIH HHS / United States
R01 DA034231 / DA / NIDA NIH HHS / United States
P20 GM103501 / GM / NIGMS NIH HHS / United States
K02DA027374 / DA / NIDA NIH HHS / United States