title: The HDAC6/APOBEC3G complex regulates HIV-1 infectiveness by inducing Vif autophagic degradation.
abstract: BACKGROUND
  Human immunodeficiency virus type 1 (HIV-1) has evolved a complex strategy to overcome the immune barriers it encounters throughout an organism thanks to its viral infectivity factor (Vif), a key protein for HIV-1 infectivity and in vivo pathogenesis. Vif interacts with and promotes "apolipoprotein B mRNA-editing enzyme-catalytic, polypeptide-like 3G" (A3G) ubiquitination and subsequent degradation by the proteasome, thus eluding A3G restriction activity against HIV-1.
  
  
  RESULTS
  We found that cellular histone deacetylase 6 (HDAC6) directly interacts with A3G through its C-terminal BUZ domain (residues 841-1,215) to undergo a cellular co-distribution along microtubules and cytoplasm. The HDAC6/A3G complex occurs in the absence or presence of Vif, competes for Vif-mediated A3G degradation, and accounts for A3G steady-state expression level. In fact, HDAC6 directly interacts with and promotes Vif autophagic clearance, thanks to its C-terminal BUZ domain, a process requiring the deacetylase activity of HDAC6. HDAC6 degrades Vif without affecting the core binding factor β (CBF-β), a Vif-associated partner reported to be key for Vif- mediated A3G degradation. Thus HDAC6 antagonizes the proviral activity of Vif/CBF-β-associated complex by targeting Vif and stabilizing A3G. Finally, in cells producing virions, we observed a clear-cut correlation between the ability of HDAC6 to degrade Vif and to restore A3G expression, suggesting that HDAC6 controls the amount of Vif incorporated into nascent virions and the ability of HIV-1 particles of being infectious. This effect seems independent on the presence of A3G inside virions and on viral tropism.
  
  
  CONCLUSIONS
  Our study identifies for the first time a new cellular complex, HDAC6/A3G, involved in the autophagic degradation of Vif, and suggests that HDAC6 represents a new antiviral factor capable of controlling HIV-1 infectiveness by counteracting Vif and its functions.
authors.affiliation: Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Departamento de Medicina Física y Farmacología, Facultad de Medicina, Universidad de La Laguna (ULL), Campus de Ofra s/n, 38071, La Laguna, Tenerife, Spain. missmariasoledad@gmail.com.
authors.forename: María-Soledad
authors.initials: MS
authors.lastname: Valera
authors.affiliation: Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Departamento de Medicina Física y Farmacología, Facultad de Medicina, Universidad de La Laguna (ULL), Campus de Ofra s/n, 38071, La Laguna, Tenerife, Spain. laura.spm@gmail.com.
authors.forename: Laura
authors.initials: L
authors.lastname: de Armas-Rillo
authors.affiliation: Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Departamento de Medicina Física y Farmacología, Facultad de Medicina, Universidad de La Laguna (ULL), Campus de Ofra s/n, 38071, La Laguna, Tenerife, Spain. jbarrosox@gmail.com.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barroso-González
authors.affiliation: Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Departamento de Medicina Física y Farmacología, Facultad de Medicina, Universidad de La Laguna (ULL), Campus de Ofra s/n, 38071, La Laguna, Tenerife, Spain. serena.ziglio@gmail.com.
authors.forename: Serena
authors.initials: S
authors.lastname: Ziglio
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 15 rue René Descartes, 67084, Strasbourg, France. julien.batisse@igbmc.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Batisse
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 15 rue René Descartes, 67084, Strasbourg, France. Noe.dubois1990@gmail.com.
authors.forename: Noé
authors.initials: N
authors.lastname: Dubois
authors.affiliation: Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Departamento de Medicina Física y Farmacología, Facultad de Medicina, Universidad de La Laguna (ULL), Campus de Ofra s/n, 38071, La Laguna, Tenerife, Spain. saramh222@gmail.com.
authors.forename: Sara
authors.initials: S
authors.lastname: Marrero-Hernández
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS) UMR5236 CNRS UMSF, 1919 route de Mende, 34293, Montpellier Cedex 5, France. sophieborel1@hotmail.com.
authors.forename: Sophie
authors.initials: S
authors.lastname: Borel
authors.affiliation: Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Departamento de Medicina Física y Farmacología, Facultad de Medicina, Universidad de La Laguna (ULL), Campus de Ofra s/n, 38071, La Laguna, Tenerife, Spain. lauratfe@gmail.com.
authors.forename: Laura
authors.initials: L
authors.lastname: García-Expósito
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS) UMR5236 CNRS UMSF, 1919 route de Mende, 34293, Montpellier Cedex 5, France. Martine.Biard@cpbs.cnrs.fr.
authors.forename: Martine
authors.initials: M
authors.lastname: Biard-Piechaczyk
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 15 rue René Descartes, 67084, Strasbourg, France. jc.paillart@ibmc-cnrs.unistra.fr.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Paillart
authors.affiliation: Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Departamento de Medicina Física y Farmacología, Facultad de Medicina, Universidad de La Laguna (ULL), Campus de Ofra s/n, 38071, La Laguna, Tenerife, Spain. avalenzu@ull.edu.es.
authors.forename: Agustín
authors.initials: A
authors.lastname: Valenzuela-Fernández
mesh_terms: D000071480:APOBEC-3G Deaminase; D001343:Autophagy; D002460:Cell Line; D003564:Cytidine Deaminase / Q000378:metabolism*; D004847:Epithelial Cells / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D011485:Protein Binding; D025941:Protein Interaction Mapping; D059748:Proteolysis; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase