HIV- 1 protease inhibits Cap- and poly(A)-dependent translation upon eIF4GI and PABP cleavage

• Published in: PloS one 2009-11, Vol.4 (11), p.e7997-e7997
• Main Authors: Castelló, Alfredo, Franco, David, Moral-López, Pablo, Berlanga, Juan J, Alvarez, Enrique, Wimmer, Eckard, Carrasco, Luis
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Cell-free system; Cellular proteins; Cleavage; Encephalomyocarditis virus; Encephalomyocarditis virus - genetics; Eukaryotic Initiation Factor-4G - metabolism; Gag protein; Gene expression; Gene Products, gag - chemistry; HeLa Cells; Hepatitis; HIV; HIV Protease - metabolism; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Hydrolysis; Inhibition; Initiation factor eIF-4G; Initiation factors; Internal ribosome entry site; Kinases; Luciferases - metabolism; Messenger RNA; mRNA; Plasmids; Plasmids - metabolism; Poly A - metabolism; Poly(A)-binding protein; Poly(A)-Binding Proteins - metabolism; Polyadenine; Polyadenylation; Protease; Proteases; Protein binding; Protein Biosynthesis; Protein synthesis; Proteinase; Proteins; Proteolysis; Recombinant Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Transcription; Translation (Genetics); Viral proteins; Virology; Virology/Effects of Virus Infection on Host Gene Expression; Virology/Immunodeficiency Viruses; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0007997

A number of viral proteases are able to cleave translation initiation factors leading to the inhibition of cellular translation. This is the case of human immunodeficiency virus type 1 protease (HIV-1 PR), which hydrolyzes eIF4GI and poly(A)-binding protein (PABP). Here, the effect of HIV-1 PR on cellular and viral protein synthesis has been examined using cell-free systems. HIV-1 PR strongly hampers translation of pre-existing capped luc mRNAs, particularly when these mRNAs contain a poly(A) tail. In fact, HIV-1 PR efficiently blocks cap- and poly(A)-dependent translation initiation in HeLa extracts. Addition of exogenous PABP to HIV-1 PR treated extracts partially restores the translation of polyadenylated luc mRNAs, suggesting that PABP cleavage is directly involved in the inhibition of poly(A)-dependent translation. In contrast to these data, PABP cleavage induced by HIV-1 PR has little impact on the translation of polyadenylated encephalomyocarditis virus internal ribosome entry site (IRES)-containing mRNAs. In this case, the loss of poly(A)-dependent translation is compensated by the IRES transactivation provided by eIF4G cleavage. Finally, translation of capped and polyadenylated HIV-1 genomic mRNA takes place in HeLa extracts when eIF4GI and PABP have been cleaved by HIV-1 PR. Together these results suggest that proteolytic cleavage of eIF4GI and PABP by HIV-1 PR blocks cap- and poly(A)-dependent initiation of translation, leading to the inhibition of cellular protein synthesis. However, HIV-1 genomic mRNA can be translated under these conditions, giving rise to the production of Gag polyprotein.