HCMV and the Activation of the PI3KAktTSCmTORC1 Pathway

HCMV infection has dramatic effects on the PI3K-Akt-TSC-mTORC 1 pathway. HCMV infection activates Akt through stimulation of T308 phosphorylation via activation of PI3K (Johnson et al. 2001; Yu and Alwine 2002) and stimulation of S473 phosphorylation via activation of mTORC2 (Kudchodkar et al. 2006) (Fig. 1). This occurs by at least two mechanisms. First, transient activation occurs via HCMV attachment to cell receptors which mediate signaling to PI3K (Johnson et al. 2001). However, the identity of this receptor and the means of activating PI3K are under debate (Isaacson et al. 2007; see the chapter by M.K. Isaacson et al., this volume). Second, long-term activation results from the expression of HCMV encoded proteins (Yu and Alwine 2002; Kudchodkar et al. 2006); for example, transfection experiments have shown that expression of the individual major immediate early proteins (either the 72-kDa IE1 or the 86-kDa IE2 proteins) can stimulate phosphorylation of Akt at both sites (Yu and Alwine 2002; Y. Yu and J.C. Alwine, unpublished data).

The HCMV-induced activation of Akt leads to the activation of mTORC1, as indicated by phosphorylation of 4E-BP and S6K, beginning 8-12 h postinfection

Fig. 3 The effects of stress inducers and HCMV infection on the PI3K-Akt-mTOR pathway, its associated substrates and the components of the eIF4F complex. Stress inducers (green) are shown at sites where they affect the PI3K-Akt-mTOR pathway. The points shown in red indicate where HCMV infection exerts its effects; Table 1 presents a synopsis of each, see text for details

Fig. 3 The effects of stress inducers and HCMV infection on the PI3K-Akt-mTOR pathway, its associated substrates and the components of the eIF4F complex. Stress inducers (green) are shown at sites where they affect the PI3K-Akt-mTOR pathway. The points shown in red indicate where HCMV infection exerts its effects; Table 1 presents a synopsis of each, see text for details

(Kudchodkar et al. 2004). Although Akt activation is necessary to maintain cap-dependent translation, it is not sufficient. The virus must do more since mTOR kinase activity can be inhibited by many stress responses which exert their effects at points downstream of Akt in the signaling pathway (Fig. 3). Stress responses that do this are induced by the following conditions:

Was this article helpful?

0 0

Post a comment