4.6 Article

Protein Phosphatase 1 Regulates Human Cytomegalovirus Protein Translation by Restraining AMPK Signaling

Journal

FRONTIERS IN MICROBIOLOGY
Volume 12, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2021.698603

Keywords

PP1; HCMV; AMPK; phosphatase; tegument; eEF2

Categories

Funding

  1. Medical University of Vienna
  2. Austrian Science Fund (FWF) [P33546]
  3. NIH [1R01HL125005, 5U54MD007597, AI117970]
  4. DOC Fellowship of the Austrian Academy of Sciences at the Department of Internal Medicine I of the Medical University of Vienna
  5. Austrian Science Fund (FWF) [P33546] Funding Source: Austrian Science Fund (FWF)

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In this study, the researchers found that inhibition of PP1 using 1E7-03 severely impaired HCMV replication and viral protein translation, potentially through preventing AMP-activated protein kinase dephosphorylation. This revealed an important mechanism of PP1 for lytic HCMV infection.
Human cytomegalovirus (HCMV) carries the human protein phosphatase 1 (PP1) and other human proteins important for protein translation in its tegument layer for a rapid supply upon infection. However, the biological relevance behind PP1 incorporation and its role during infection is unclear. Additionally, PP1 is a difficult molecular target due to its promiscuity and similarities between the catalytic domain of multiple phosphatases. In this study, we circumvented these shortcomings by using 1E7-03, a small molecule protein-protein interaction inhibitor, as a molecular tool of noncatalytic PP1 inhibition. 1E7-03 treatment of human fibroblasts severely impaired HCMV replication and viral protein translation. More specifically, PP1 inhibition led to the deregulation of metabolic signaling pathways starting at very early time points post-infection. This effect was at least partly mediated by the prevention of AMP-activated protein kinase dephosphorylation, leading to elongation factor 2 hyperphosphorylation and reduced translation rates. These findings reveal an important mechanism of PP1 for lytic HCMV infection.

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