Poly(A) binding protein abundance regulates eukaryotic translation initiation factor 4F assembly in human cytomegalovirus-infected cells

Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5627-32. doi: 10.1073/pnas.1202829109. Epub 2012 Mar 19.

Abstract

By commandeering cellular translation initiation factors, or destroying those dispensable for viral mRNA translation, viruses often suppress host protein synthesis. In contrast, cellular protein synthesis proceeds in human cytomegalovirus (HCMV)-infected cells, forcing viral and cellular mRNAs to compete for limiting translation initiation factors. Curiously, inactivating the host translational repressor 4E-BP1 in HCMV-infected cells stimulates synthesis of the cellular poly(A) binding protein (PABP), significantly increasing PABP abundance. Here, we establish that new PABP synthesis is translationally controlled by the HCMV-encoded UL38 mammalian target of rapamycin complex 1-activator. The 5' UTR within the mRNA encoding PABP contains a terminal oligopyrimidine (TOP) element found in mRNAs, the translation of which is stimulated in response to mitogenic, growth, and nutritional stimuli, and proteins encoded by TOP-containing mRNAs accumulated in HCMV-infected cells. Furthermore, UL38 expression was necessary and sufficient to regulate expression of a PABP TOP-containing reporter. Remarkably, preventing the rise in PABP abundance by RNAi impaired eIF4E binding to eIF4G, thereby reducing assembly of the multisubunit initiation factor eIF4F, viral protein production, and replication. This finding demonstrates that viruses can increase host translation initiation factor concentration to foster their replication and defines a unique mechanism whereby control of PABP abundance regulates eIF4F assembly.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Capsid Proteins / metabolism
  • Cytomegalovirus / physiology*
  • Cytomegalovirus Infections / metabolism*
  • Cytomegalovirus Infections / virology*
  • Eukaryotic Initiation Factor-4E / metabolism
  • Eukaryotic Initiation Factor-4F / metabolism*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes
  • Poly(A)-Binding Protein I / metabolism*
  • Protein Binding
  • Protein Biosynthesis / genetics
  • Proteins / metabolism
  • RNA 5' Terminal Oligopyrimidine Sequence / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • TOR Serine-Threonine Kinases
  • Virus Replication

Substances

  • Capsid Proteins
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factor-4F
  • Multiprotein Complexes
  • Poly(A)-Binding Protein I
  • Proteins
  • RNA, Messenger
  • UL38 protein, human herpesvirus-5
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases