Cellular Protein Phosphatase 2A Regulates Cell Survival Mechanisms in Influenza A Virus Infection

Abstract

Influenza A viruses (IAVs) are respiratory pathogens that are able to hijack multiple cellular mechanisms to drive their replication. Consequently, several viral and cellular proteins undergo posttranslational modifications such as dynamic phosphorylation/dephosphorylation. In eukaryotic cells, dephosphorylation is mainly catalyzed by protein phosphatase 2A (PP2A). While the function of kinases in IAV infection is quite well studied, only little is known about the role of PP2A in IAV replication. Here, we show, by using knockdown and inhibition approaches of the catalytic subunit PP2Ac, that this phosphatase is important for efficient replication of several IAV subtypes. This could neither be attributed to alterations in the antiviral immune response nor to changes in transcription or translation of viral genes. Interestingly, decreased PP2Ac levels resulted in a significantly reduced cell viability after IAV infection. Comprehensive kinase activity profiling identified an enrichment of process networks related to apoptosis and indicated a synergistic action of hyper-activated PI3K/Akt, MAPK/JAK-STAT and NF-kB signaling pathways, collectively resulting in increased cell death. Taken together, while IAV seems to effectively tap leftover PP2A activity to ensure efficient viral replication, reduced PP2Ac levels fail to orchestrate cell survival mechanisms to protect infected cells from early cell death.

Proteomic and phosphoproteomic profilings reveal distinct cellular responses during Tilapinevirus tilapiae entry and replication

“…In the RHTiB cells, infection by TiLV prompted a distinct cellular response compared to the E-11 cells. Specifically, at 10 mpi, there was a suppression of the protein PPP2R2A, an enzyme involved in the dephosphorylation of intracellular proteins 61 , and MTHFD2, which plays a role in RNA metabolism and translation 62 . Previous research has demonstrated that the downregulation of protein phosphatase leads to cell senescence in aging zebrafish neuronal cells 63 , and the suppression of MTHFD2 has been linked to cell death in infectious hematopoietic necrosis virus (IHNV)-infected zebrafish larvae 64 .…”

“…Previous research has demonstrated that the downregulation of protein phosphatase leads to cell senescence in aging zebrafish neuronal cells 63 , and the suppression of MTHFD2 has been linked to cell death in infectious hematopoietic necrosis virus (IHNV)-infected zebrafish larvae 64 . Thus, the suppression of these proteins in infected RHTiB cells indicates that TiLV may inhibit host cell replication and metabolism early in the infection process, which facilitates viral entry and replication, as seen with other viruses, such as influenza A virus, hepatitis B, and Epstein-Barr virus (EBV) 61,[65][66][67] . Additionally, at 10 mpi, the TiLV-infected RHTiB cells showed inhibition of cytoskeletal proteins, including BCAS3, which controls the direction of cell migration 68 .…”

Role of Signaling Pathways in the Viral Life Cycle 2.0

“…Both the paper by Harris and colleges and the paper by Gerlt and coworkers deal with the respiratory pathogen IAV [ 9 , 10 ]. The host innate immune response is essential to inhibit IAV replication.…”

“…The age- and strain-dependent attenuation of the innate immune responses to IAV infection in mice reflects the phenotypic differences in infected young and old mice and suggests that the decline in innate immunity functions in elderly may contribute to the increased susceptibility to influenza [ 9 ]. Gerlt and colleges studied the role of protein phosphatase 2A (PP2A) in IAV replication [ 10 ]. By using RNA interference-mediated knockdown of the catalytic subunit of PP2A or the inhibition of PP2A by okadaic acid, the authors found that PP2A exhibited a supportive role in IAV replication in cells by increasing cell survival after viral infection.…”