Transactive Response DNA-Binding Protein (TARDBP/TDP-43) Regulates Cell Permissivity to HIV-1 Infection by Acting on HDAC6

Transactive Response DNA-Binding Protein (TARDBP/TDP-43) Regulates Cell Permissivity to HIV-1 Infection by Acting on HDAC6

The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-...

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Bibliographic Details
Main Authors: Romina Cabrera-Rodríguez, Silvia Pérez-Yanes, Rafaela Montelongo, José M. Lorenzo-Salazar, Judith Estévez-Herrera, Jonay García-Luis, Antonio Íñigo-Campos, Luis A. Rubio-Rodríguez, Adrián Muñoz-Barrera, Rodrigo Trujillo-González, Roberto Dorta-Guerra, Concha Casado, María Pernas, Julià Blanco, Carlos Flores, Agustín Valenzuela-Fernández
Format: Article
Language:English
Published: MDPI AG 2022-05-01
Series:International Journal of Molecular Sciences
Subjects:
TARDBP/TDP-43
HDAC6
pore fusion formation
cell-permissivity
HIV-1 infection
Online Access:https://www.mdpi.com/1422-0067/23/11/6180
Description
Summary:The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-TDP-43 increased both mRNA and protein levels of HDAC6, resulting in impaired HIV-1 infection independently of the viral envelope glycoprotein complex (Env) tropism. Consistently, using an HIV-1 Env-mediated cell-to-cell fusion model, the overexpression of TDP-43 levels negatively affected viral Env fusion capacity. Silencing of endogenous TDP-43 significantly decreased HDAC6 levels and increased the fusogenic and infection activities of the HIV-1 Env. Using pseudovirus bearing primary viral Envs from HIV-1 individuals, overexpression of wt-TDP-43 strongly reduced the infection activity of Envs from viremic non-progressors (VNP) and rapid progressors (RP) patients down to the levels of the inefficient HIV-1 Envs observed in long-term non-progressor elite controllers (LTNP-EC). On the contrary, silencing endogenous TDP-43 significantly favored the infectivity of primary Envs from VNP and RP individuals, and notably increased the infection of those from LTNP-EC. Taken together, our results indicate that TDP-43 shapes cell permissivity to HIV-1 infection, affecting viral Env fusion and infection capacities by altering the HDAC6 levels and associated tubulin-deacetylase anti-HIV-1 activity.
ISSN:1661-6596
1422-0067

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