Human Cytomegalovirus Infection Alters the Substrate Specificities and Rapamycin Sensitivities of Raptorand Rictor-Containing Complexes

Signaling mediated by the mammalian target of rapamycin kinase (mTOR) is activated during human cytomegalovirus (HCMV) infection. mTOR is found in two complexes differing by the binding partner, rictor or raptor. Activated mTOR-raptor promotes capdependent translation through the hyperphosphorylatio...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 103; no. 38; pp. 14182 - 14187
Main Authors Kudchodkar, Sagar B., Yu, Yongjun, Maguire, Tobi G., Alwine, James C.
Format Journal Article
LanguageEnglish
Published National Academy of Sciences 19.09.2006
Subjects
Antibodies
Antivirals
Birds of prey
Infections
Phosphorylation
RNA
Substrate specificity
Viral infections
Viral proteins
Viruses
Online AccessGet full text

Cover

More Information
Summary:Signaling mediated by the mammalian target of rapamycin kinase (mTOR) is activated during human cytomegalovirus (HCMV) infection. mTOR is found in two complexes differing by the binding partner, rictor or raptor. Activated mTOR-raptor promotes capdependent translation through the hyperphosphorylation of the elF4E-binding protein (4E-BP). This activity of the raptor complex is normally inhibited by cell stress responses or the drug rapamycin. However, we previously showed that this inhibition of mTOR signaling can be circumvented during HCMV infection such that hyperphosphorylation of 4E-BP is maintained. Here we show that HCMV infection also activates the rictor complex, as indicated by increased phosphorylation of Akt S473; this phosphorylation is insensitive to rapamycin but sensitive to caffeine in both uninfected and infected cells. By using short-hairpin RNAs to deplete rictor and raptor, we find that rictor is more significant than raptor for the viral infection. Surprisingly, the inhibitory effects of rapamycin on viral growth are primarily due to the presence of rictor, not raptor. Raptor and rictor depletion experiments show that in HCMV-infected cells, both raptor- and rictor-containing complexes can mediate the hyperphosphorylation of 4E-BP and the phosphorylation of p70S6 kinase. Under these conditions, the rictor complex is rapamycin-sensitive for the hyperphosphorylation of 4E-BP, but the raptor complex is not. These data suggest that, during HCMV infection, the rictor- and raptor-containing complexes are modified such that their substrate specificities and rapamycin sensitivities are altered. Our data also suggest that the present understanding of rapamycin's inhibitory effects is incomplete.
ISSN:0027-8424
1091-6490