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

Ferdous Kadri,Marco Pacifici,Anna Wilk,Amanda Parker-Struckhoff,Luis Del Valle,Kurt F Hauser,Pamela E Knapp,Christopher Parsons,Duane Jeansonne,Adam Lassak,Francesca Peruzzi

doi:10.1074/jbc.m115.675751

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.

Highlights

Neuro-inflammation and cognitive impairment caused by HIV-1 infection persist despite the use of antiretroviral therapies [1, 2], and importantly, these therapies do not limit the amount of HIV Tat in the brain [3, 4] where it contributes to chronic immune activation [4]
TAU 3R Isoforms Are Increased and SC35 Is Dysregulated in Human Frontal Cortex with HIV-Encephalitis—Because dysregulation of the TAU 3R:4R ratios is highly correlative with many neurodegenerative diseases [9], we investigated the expression of TAU 3R and 4R in brain samples from HIVϩ patients with encephalitis (HIVE, n ϭ 4) and controls (HIVϪ and HIVϩ patients without brain pathology; n ϭ 4 each group)
Immunohistochemical analysis of FFPE sections labeled with anti-TAU RD3 (3R)- and anti-TAU RD4 (4R)-specific antibodies (Fig. 1, A and B, respectively) revealed TAU 3R to be preferentially increased in HIV-encephalitis (HIVE) cases in respect to controls, the increase in 4R was less apparent because controls demonstrated relatively high levels of this splicing variant

Summary

Introduction

Neuro-inflammation and cognitive impairment caused by HIV-1 infection persist despite the use of antiretroviral therapies [1, 2], and importantly, these therapies do not limit the amount of HIV Tat in the brain [3, 4] where it contributes to chronic immune activation [4]. We report increased phosphorylation of SC35 and altered Tau 3R:4R ratios in brain tissues from individuals with HIV-encephalitis, in an inducible Tat-transgenic mouse model and in neuronal cell cultures.

Results

Conclusion