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PUBLICATION IN NATURE COMMUNICATIONS (IF=12.35)

Bruno BEAUMELLE publishes an article in Nature Communications (IF=12.35):  Cyclophilin A enables specific HIV-1 Tat palmitoylation and accumulation in uninfected cells (Chopard et al, 2018)

www.nature.com/articles/s41467-018-04674-y

 

Most HIV-1 Tat is secreted by infected cells, and circulating Tat acts as a viral toxin. Circulating Tat inhibits for instance neuromediator secretion by neurons and phagocytosis by macrophages. Tat is thus likely involved in the development of neuronal disorders and opportunistic infections in HIV-1 patients. We previously showed that Tat secretion is unconventional and takes place directly across the plasma membrane where Tat is recruited by phosphatidylinositol (4,5) bisphosphate (PIP2). Circulating Tat can be internalized by most cell types using endocytosis. Tat will cross the endosome membrane to reach the cytosol and bind PIP2.

In the study published by Nature Communications (2018) we showed that, once on PIP2, Tat is palmitoylated in target cells such as neurons and macrophages. This modification enables Tat to become resident on PIP2. Tat palmitoylation inhibits its secretion and is required for Tat to inhibit phagocytosis and neurosecretion. These two membrane processes indeed largely rely on cell proteins whose recruitment by PIP2 is inhibited by palmitoylated Tat that has a very strong affinity for PIP2. Tat palmitoylation is performed by an acyl-transferase (DHHC20) with an essential cofactor, cyclophilin A (CypA). In infected cells CypA binds to the HIV-1 capsid protein and is thereby encapsidated. Viral budding efficiency is so high that it will export all cell CypA. Tat palmitoylation de Tat is thus inhibited in infected cells allowing strong Tat secretion.

 

 


     
   

   

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Institut de Recherche en Infectiologie de Montpellier
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