TDP-43 Controls HIV-1 Viral Production and Virus Infectiveness

• Published in: International journal of molecular sciences Vol. 24; no. 8; p. 7658
• Main Authors: Cabrera-Rodríguez, Romina, Pérez-Yanes, Silvia, Lorenzo-Sánchez, Iria, Estévez-Herrera, Judith, García-Luis, Jonay, Trujillo-González, Rodrigo, Valenzuela-Fernández, Agustín
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.04.2023; MDPI
• Subjects: Control; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzymes; Gene Products, gag - genetics; Genetic translation; Health aspects; HIV (Viruses); MicroRNA; Protein binding; Protein Processing, Post-Translational; RNA, Messenger - metabolism; Philippines; TARDBP/TDP-43; autophagy; viral production; HDAC6; HIV-1 infection capacity
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms24087658

The transactive response DNA-binding protein (TARDBP/TDP-43) is known to stabilize the anti-HIV-1 factor, histone deacetylase 6 (HDAC6). TDP-43 has been reported to determine cell permissivity to HIV-1 fusion and infection acting on tubulin-deacetylase HDAC6. Here, we studied the functional involvement of TDP-43 in the late stages of the HIV-1 viral cycle. The overexpression of TDP-43, in virus-producing cells, stabilized HDAC6 (i.e., mRNA and protein) and triggered the autophagic clearance of HIV-1 Pr55Gag and Vif proteins. These events inhibited viral particle production and impaired virion infectiveness, observing a reduction in the amount of Pr55Gag and Vif proteins incorporated into virions. A nuclear localization signal (NLS)-TDP-43 mutant was not able to control HIV-1 viral production and infection. Likewise, specific TDP-43-knockdown reduced HDAC6 expression (i.e., mRNA and protein) and increased the expression level of HIV-1 Vif and Pr55Gag proteins and α-tubulin acetylation. Thus, TDP-43 silencing favored virion production and enhanced virus infectious capacity, thereby increasing the amount of Vif and Pr55Gag proteins incorporated into virions. Noteworthy, there was a direct relationship between the content of Vif and Pr55Gag proteins in virions and their infection capacity. Therefore, for TDP-43, the TDP-43/HDAC6 axis could be considered a key factor to control HIV-1 viral production and virus infectiveness.