title: HIV-1-Tat Protein Inhibits SC35-mediated Tau Exon 10 Inclusion through Up-regulation of DYRK1A Kinase.
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.
authors.affiliation: From the Department of Medicine, Stanley S. Scott Cancer Center, and Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112 and.
authors.forename: Ferdous
authors.initials: F
authors.lastname: Kadri
authors.affiliation: From the Department of Medicine, Stanley S. Scott Cancer Center, and.
authors.forename: Marco
authors.initials: M
authors.lastname: Pacifici
authors.affiliation: From the Department of Medicine, Stanley S. Scott Cancer Center, and.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilk
authors.affiliation: From the Department of Medicine, Stanley S. Scott Cancer Center, and.
authors.forename: Amanda
authors.initials: A
authors.lastname: Parker-Struckhoff
authors.affiliation: From the Department of Medicine, Stanley S. Scott Cancer Center, and.
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.affiliation: the Departments of Pharmacology and Toxicology and.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.affiliation: Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia 23284.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: From the Department of Medicine, Stanley S. Scott Cancer Center, and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Parsons
authors.affiliation: From the Department of Medicine, Stanley S. Scott Cancer Center, and.
authors.forename: Duane
authors.initials: D
authors.lastname: Jeansonne
authors.affiliation: From the Department of Medicine, Stanley S. Scott Cancer Center, and.
authors.forename: Adam
authors.initials: A
authors.lastname: Lassak
authors.affiliation: From the Department of Medicine, Stanley S. Scott Cancer Center, and fperuz@lsuhsc.edu.
authors.forename: Francesca
authors.initials: F
authors.lastname: Peruzzi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000821:virology; D005091:Exons; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012261:Ribonucleoproteins; D000068103:Serine-Arginine Splicing Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D016875:tau Proteins; D000097603:Dyrk Kinases; C054369:MAPT protein, human; C558298:Mapt protein, mouse; C499372:SRSF2 protein, mouse; C073288:SRSF2 protein, human
keywords: DYRK1A; RNA splicing; Tau protein (Tau); human immunodeficiency virus (HIV); phosphorylation