RT info:eu-repo/semantics/article
T1 HIV-1 Nef Targets HDAC6 to Assure Viral Production and Virus Infection.
A1 Valenzuela Fernández, Agustín
A1 Marrero Hernández, Sara
A1 Márquez Arce, Daniel
A1 Cabrera Rodríguez, Romina
A1 Estévez Herrera, Judith
A1 Pérez Yanes, Silvia
A1 Barroso González, Jonathan
A1 Madrid, Ricardo
A1 Machado, José David
A1 Blanco, Julià
A2 Medicina Física y Farmacología
A2 Grupo "Inmunología Celular y Viral".
K1 HIV-1
K1 Nef
K1 HDAC6
K1 Pr55Gag
K1 acidic-endocytic/lysosomal degradation
K1 autophagy
K1 infection
K1 viral production
AB HIV Nef is a central auxiliary protein in HIV infection and pathogenesis. Our resultsindicate that HDAC6 promotes the aggresome/autophagic degradation of the viralpolyprotein Pr55Gag to inhibit HIV-1 production. Nef counteracts this antiviral activityof HDAC6 by inducing its degradation and subsequently stabilizing Pr55Gag and Vifviral proteins. Nef appears to neutralize HDAC6 by an acidic/endosomal-lysosomalprocessing and does not need the downregulation function, since data obtained withthe non-associated cell-surface Nef-G2A mutant – the cytoplasmic location of HDAC6 –together with studies with chemical inhibitors and other Nef mutants, point to thisdirection. Hence, the polyproline rich region P72xxP75 (69–77 aa) and the di-Leucinmotif in the Nef-ExxxLL160-165 sequence of Nef, appear to be responsible for HDAC6clearance and, therefore, required for this novel Nef proviral function. Nef and NefG2A co-immunoprecipitate with HDAC6, whereas the Nef-PPAA mutant showed areduced interaction with the anti-HIV-1 enzyme. Thus, the P72xxP75 motif appears tobe responsible, directly or indirectly, for the interaction of Nef with HDAC6. Remarkably,by neutralizing HDAC6, Nef assures Pr55Gag location and aggregation at plasmamembrane, as observed by TIRFM, promotes viral egress, and enhances the infectivityof viral particles. Consequently, our results suggest that HDAC6 acts as an anti-HIV-1restriction factor, limiting viral production and infection by targeting Pr55Gag and Vif.This function is counteracted by functional HIV-1 Nef, in order to assure viral productionand infection capacities. The interplay between HIV-1 Nef and cellular HDAC6 maydetermine viral infection and pathogenesis, representing both molecules as key targetsto battling HIV
YR 2019
FD 2019
LK http://riull.ull.es/xmlui/handle/915/35328
UL http://riull.ull.es/xmlui/handle/915/35328
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 26-dic-2024