Human cytomegalovirus attenuates AKT activity by destabilizing insulin receptor substrate proteins

Read the full article See related articles

Listed in

This article is not in any list yet, why not save it to one of your lists.
Log in to save this article


The phosphoinositide 3-kinase (PI3K)/AKT pathway plays crucial roles in cell viability and protein synthesis and is frequently co-opted by viruses to support their replication. Although many viruses maintain high levels of AKT activity during infection, other viruses, such as vesicular stomatitis virus and human cytomegalovirus (HCMV), cause AKT to accumulate in an inactive state. To efficiently replicate, HCMV requires FoxO transcription factors to localize to the infected cell nucleus (Zhang et al. mBio 2022), a process that is antagonized by AKT. Here, we investigated how HCMV inactivates AKT to achieve this. Results from subcellular fractionation and live-cell imaging studies indicated a defect in the recruitment of AKT to membranes upon serum stimulation of HCMV-infected cells. UV-inactivated virions failed to inactivate AKT, suggesting a requirement for de novo viral gene expression. Through additional studies, we identify that UL38 (pUL38), a viral activator of mTORC1, inactivates AKT by destabilizing insulin receptor substrate-1 (IRS1), a protein that recruits PI3K to growth factor receptors. Decreased electrophoretic mobility and diminished expression of IRS1 correlated with the accumulation of UL38 protein during infection. However, destabilization of IRS1 and loss of AKT activity did not occur in cells infected with an HCMV mutant disrupted for UL38 nor when mTORC1 was inhibited by rapamycin. Finally, ectopic expression of UL38 in uninfected cells sufficed to cause IRS1 degradation and AKT inactivation, and these effects were likewise reversed by rapamycin. Collectively, our results demonstrate that HCMV relies upon a cell-intrinsic negative feedback loop to render AKT inactive during productive infection.


Human cytomegalovirus (HCMV) requires inactivation of AKT to efficiently replicate, yet how AKT is shut off during HCMV infection has remained unclear. We show that UL38, an HCMV protein that activates mTORC1, is necessary and sufficient to destabilize insulin receptor substrate 1 (IRS1), a model insulin receptor substrate (IRS) protein. Degradation of IRS proteins in settings of excessive mTORC1 activity is an important mechanism for insulin resistance. When IRS proteins are destabilized, PI3K cannot be recruited to growth factor receptor complexes, and hence, AKT membrane recruitment, a rate limiting step in its activation, fails to occur. Despite its penchant for remodeling host cell signaling pathways, our results reveal that HCMV relies upon a cell-intrinsic negative regulatory feedback loop to inactivate AKT. Given that pharmacological inhibition of PI3K/AKT potently induces HCMV reactivation from latency, our findings also imply that the expression of UL38 activity must be tightly regulated within latently infected cells to avoid spontaneous reactivation.

Article activity feed