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Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods
Published on: December 21, 2019
Cellular serine/threonine phosphatase activity during human cytomegalovirus infection
1Divisions of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. mhakki@fhcrc.org
Abstract:
While the importance of cellular and viral kinases in HCMV replication has been demonstrated, relatively little is known about the activity of cellular phosphatases. We conducted a series of experiments designed to investigate the effect of HCMV infection on cellular serine/threonine phosphatase activity. We found that the abundance of two major cellular serine/threonine phosphatases, PP1 and PP2A, increases during HCMV infection. This was associated with an increase in threonine phosphatase activity in HCMV-infected cells. HCMV infection conferred resistance to the effects of the phosphatase inhibitors calyculin A (CA) and okadaic acid with regards to global protein hyperphosphorylation and the shutoff of protein synthesis. The protective effect of HCMV infection could be overcome at a high concentration of CA, suggesting that cellular phosphatase activity is required for critical cellular processes during HCMV infection. Specifically, phosphatase activity was required to limit the accumulation of phospho-eIF2alpha, but not phospho-PKR, during HCMV infection.
Insights
Human cytomegalovirus (HCMV) infection increases cellular serine/threonine phosphatase activity, specifically PP1 and PP2A, which is crucial for viral replication and protein synthesis regulation.
Area of Science:
- Virology
- Cell Biology
- Biochemistry
Background:
- Cellular kinases are vital for HCMV replication, but the role of cellular phosphatases remains largely unexplored.
- Understanding phosphatase activity during HCMV infection is crucial for comprehending viral pathogenesis.
Purpose of the Study:
- To investigate the impact of HCMV infection on cellular serine/threonine phosphatase activity.
- To determine the role of cellular phosphatases in HCMV replication and host cell processes.
Main Methods:
- Assessing the abundance and activity of cellular phosphatases (PP1, PP2A) in HCMV-infected cells.
- Evaluating the effect of phosphatase inhibitors (calyculin A, okadaic acid) on infected cells.
- Analyzing protein phosphorylation patterns, including phospho-eIF2alpha and phospho-PKR.
Main Results:
- HCMV infection significantly increased the abundance and activity of cellular serine/threonine phosphatases PP1 and PP2A.
- HCMV-infected cells exhibited resistance to phosphatase inhibitors, maintaining protein synthesis and avoiding hyperphosphorylation.
- Cellular phosphatase activity was essential for limiting phospho-eIF2alpha accumulation during HCMV infection.
Conclusions:
- HCMV infection modulates cellular phosphatase activity, enhancing PP1 and PP2A levels and activity.
- Cellular phosphatases play a critical role in regulating host cell processes, including protein synthesis, during HCMV infection.
- Targeting cellular phosphatases may offer novel therapeutic strategies against HCMV.
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