Department of Microbiology and Immunology, Louisiana State University Health Sciences Center Shreveport , Shreveport, Louisiana, USA.
Department of Immunobiology, University of Arizona , Tucson, Arizona, USA.
J Virol. 2023 Oct 31;97(10):e0056323. doi: 10.1128/jvi.00563-23. Epub 2023 Sep 27.
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.
人类巨细胞病毒 (HCMV) 需要使 AKT 失活才能有效地复制，但 HCMV 感染过程中如何关闭 AKT 仍然不清楚。我们发现，激活 mTORC1 的 HCMV 蛋白 UL38 是稳定胰岛素受体底物 1 (IRS1) 所必需且充分的，IRS1 是一种胰岛素受体底物 (IRS) 模型蛋白。在 mTORC1 活性过度的情况下，IRS 蛋白的降解是胰岛素抵抗的一个重要机制。当 IRS 蛋白不稳定时，PI3K 无法被招募到生长因子受体复合物中，因此，AKT 膜募集（其激活的限速步骤）无法发生。尽管 HCMV 倾向于重塑宿主细胞信号通路，但我们的结果表明，HCMV 依赖于细胞内负反馈调节环来失活 AKT。鉴于抑制 PI3K/AKT 的药理学作用可强烈诱导潜伏感染的 HCMV 重新激活，我们的发现还表明，UL38 活性的表达必须在潜伏感染细胞内受到严格调控，以避免自发重新激活。
