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

PLoS One. 2009 Nov 24;4(11):e7997. doi: 10.1371/journal.pone.0007997.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Encephalomyocarditis virus / genetics
  • Eukaryotic Initiation Factor-4G / metabolism*
  • Gene Products, gag / chemistry
  • HIV Protease / metabolism*
  • HeLa Cells
  • Humans
  • Hydrolysis
  • Luciferases / metabolism
  • Plasmids / metabolism
  • Poly A / metabolism*
  • Poly(A)-Binding Proteins / metabolism*
  • Protein Biosynthesis
  • RNA, Messenger / metabolism
  • Recombinant Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • EIF4G1 protein, human
  • Eukaryotic Initiation Factor-4G
  • Gene Products, gag
  • Poly(A)-Binding Proteins
  • RNA, Messenger
  • Recombinant Proteins
  • Poly A
  • Luciferases
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1