Activation of GCN2 upon HIV-1 infection and inhibition of translation
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Cellular and Molecular Life Sciences
RESEARCH ARTICLE
Activation of GCN2 upon HIV-1 infection and inhibition of translation Ophélie Cosnefroy · Anaïs Jaspart · Christina Calmels · Vincent Parissi · Hervé Fleury · Michel Ventura · Sandrine Reigadas · Marie-Line Andréola
Received: 4 October 2012 / Revised: 23 December 2012 / Accepted: 21 January 2013 / Published online: 17 February 2013 © Springer Basel 2013
Abstract Higher eukaryotic organisms have a variety of specific and nonspecific defense mechanisms against viral invaders. In animal cells, viral replication may be limited through the decrease in translation. Some viruses, however, have evolved mechanisms that counteract the response of the host. We report that infection by HIV-1 triggers acute decrease in translation. The human protein kinase GCN2 (eIF2AK4) is activated by phosphorylation upon HIV-1 infection in the hours following infection. Thus, infection by HIV-1 constitutes a stress that leads to the activation of GCN2 with a resulting decrease in protein synthesis. We have shown that GCN2 interacts with HIV-1 integrase (IN). Transfection of IN in amino acid-starved cells, where GCN2 Ophélie Cosnefroy and Anaïs Jaspart equally contributed to the work. Sandrine Reigadas and Marie-Line Andréola equally contributed to the work. O. Cosnefroy · A. Jaspart · C. Calmels · V. Parissi · H. Fleury · M. Ventura · S. Reigadas · M.-L. Andréola UMR 5234 CNRS; Université Bordeaux Segalen, 146 Rue Léo Saignat, 33076 Bordeaux cedex, France Present Address: O. Cosnefroy MRC National Institute for Medical Research, The Ridgeway Mill Hill, London, UK O. Cosnefroy · A. Jaspart · C. Calmels · V. Parissi · H. Fleury · M. Ventura · S. Reigadas (*) · M.-L. Andréola (*) Structure Fédérative de Recherche “TransbioMed”, Bordeaux, France e-mail: [email protected] M.-L. Andréola e-mail: [email protected] H. Fleury · S. Reigadas Laboratoire de Virologie. CHU de Bordeaux, Bordeaux, France
is activated, increases the protein synthesis level. These results point to an as yet unknown role of GCN2 as an early mediator in the cellular response to HIV-1 infection, and suggest that the virus is able to overcome the involvement of GCN2 in the cellular response by eliciting methods to maintain protein synthesis. Keywords HIV-1 · Integrase · GCN2 · Translation
Introduction Following cell infection by retroviruses, genomic viral RNA is copied by reverse transcriptase (RT) in a double-stranded proviral DNA that is inserted into the host-cell nuclear genome by the retroviral encoded enzyme integrase (IN) [1]. In addition to RT and IN, cellular and viral proteins are associated with proviral DNA in the preintegration complex (PIC). IN is necessary and sufficient in vitro for the first two steps of DNA integration: 3′-end processing, where two nucleotides are removed from each 3′-end of the two viral DNA LTRs; and strand transfer, where each 3′-processed viral DNA end is integrated in the host-cell DNA. Retroviral replication is a complex process with a
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