Human cytomegalovirus attenuates AKT activity by destabilizing insulin receptor substrate proteins

Area of Science:

• Virology
• Molecular Biology
• Cellular Signaling

Background:

• Human cytomegalovirus (HCMV) replication necessitates the inactivation of the AKT signaling pathway.
• The precise mechanism by which HCMV achieves AKT inactivation remains largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms by which HCMV inactivates AKT signaling.
• To investigate the role of the HCMV-encoded UL38 protein in AKT regulation.

Main Methods:

• Western blotting to assess protein levels and degradation.
• Immunoprecipitation to study protein interactions.
• Cell-based assays to monitor AKT activation and HCMV replication.

Main Results:

• The HCMV UL38 protein is essential and sufficient for the destabilization of insulin receptor substrate 1 (IRS1).
• Destabilization of IRS proteins impairs PI3K recruitment, thereby inhibiting AKT membrane recruitment and activation.
• HCMV utilizes a host cell-intrinsic negative feedback loop involving UL38 to control AKT inactivation.

Conclusions:

• HCMV employs a novel strategy, mediated by UL38-induced IRS1 degradation, to inactivate AKT and facilitate viral replication.
• Tight regulation of UL38 activity in latently infected cells is crucial to prevent spontaneous HCMV reactivation, as PI3K/AKT inhibition triggers reactivation.