Cyclophilin A enables specific HIV-1 Tat palmitoylation and accumulation in uninfected cells

Christophe Chopard, Phuoc Bao Viet Tong, Petra Tóth (), Malvina Schatz, Hocine Yezid, Solène Debaisieux, Clément Mettling, Antoine Gross, Martine Pugnière, Annie Tu, Jean-Marc Strub, Jean-Michel Mesnard, Nicolas Vitale and Bruno Beaumelle ()
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Christophe Chopard: Université de Montpellier-CNRS
Phuoc Bao Viet Tong: Université de Montpellier-CNRS
Petra Tóth: 5 rue Blaise Pascal
Malvina Schatz: Université de Montpellier-CNRS
Hocine Yezid: Université de Montpellier-CNRS
Solène Debaisieux: Université de Montpellier-CNRS
Clément Mettling: 141 Rue de la Cardonille
Antoine Gross: Université de Montpellier-CNRS
Martine Pugnière: 208 Rue des Apothicaires
Annie Tu: 5 rue Blaise Pascal
Jean-Marc Strub: Université de Strasbourg
Jean-Michel Mesnard: Université de Montpellier-CNRS
Nicolas Vitale: 5 rue Blaise Pascal
Bruno Beaumelle: Université de Montpellier-CNRS

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Most HIV-1 Tat is unconventionally secreted by infected cells following Tat interaction with phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2) at the plasma membrane. Extracellular Tat is endocytosed by uninfected cells before escaping from endosomes to reach the cytosol and bind PI(4,5)P2. It is not clear whether and how incoming Tat concentrates in uninfected cells. Here we show that, in uninfected cells, the S-acyl transferase DHHC-20 together with the prolylisomerases cyclophilin A (CypA) and FKBP12 palmitoylate Tat on Cys31 thereby increasing Tat affinity for PI(4,5)P2. In infected cells, CypA is bound by HIV-1 Gag, resulting in its encapsidation and CypA depletion from cells. Because of the lack of this essential cofactor, Tat is not palmitoylated in infected cells but strongly secreted. Hence, Tat palmitoylation specifically takes place in uninfected cells. Moreover, palmitoylation is required for Tat to accumulate at the plasma membrane and affect PI(4,5)P2-dependent membrane traffic such as phagocytosis and neurosecretion.

Date: 2018
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DOI: 10.1038/s41467-018-04674-y

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