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

2021 ◽  
Vol 22 (20) ◽  
pp. 11164
Author(s):  
Vanessa Gerlt ◽  
Juliane Mayr ◽  
Juliana Del Sarto ◽  
Stephan Ludwig ◽  
Yvonne Boergeling
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Protein Phosphatase ◽  
Influenza A ◽  
Protein Phosphatase 2A ◽  
Cellular Protein ◽  
Respiratory Pathogens ◽  
Antiviral Immune Response ◽  
Phosphatase 2A ◽  
Survival Mechanisms

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.

Protein Phosphatase 2A Inactivates Bcl2’s Antiapoptotic Function by Dephosphorylation and Up-Regulation of Bcl2-p53 Binding.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1436-1436
Author(s):  
Xingming Deng ◽  
Fengqin Gao ◽  
Tammy Flagg ◽  
W. Stratford May
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Okadaic Acid ◽  
Protein Phosphatase ◽  
Apoptotic Cell ◽  
Protein Phosphatase 2A ◽  
Survival Function ◽  
Phosphorylation Site ◽  
Apoptotic Cell Death ◽  
Phosphatase 2A

Abstract DNA damage-induced p53/Bcl2 interaction at the outer mitochondrial membranes results in a Bcl2 conformational change and loss of its antiapoptotic function. Our data now indicate that either treatment of cells with the protein phosphatase 2A (PP2A) inhibitor, okadaic acid (10 nM), or specific disruption of PP2A activity by the expression of SV40 small tumor antigen enhances Bcl2 phosphorylation and suppresses the cisplatin-stimulated Bcl2-p53 interaction in association with prolonged cell survival. By contrast, C2-ceramide, a potent PP2A activator, reduces Bcl2 phosphorylation and increases Bcl2-p53 binding and promotes apoptotic cell death, suggesting that PP2A may function as a physiological regulator of Bcl2 by, at least in part, affecting its association with p53. Overexpression of the PP2A catalytic subunit (PP2A/C) suppresses Bcl2 phosphorylation in association with increased p53-Bcl2 binding and apoptotic cell death. By contrast, specific depletion of PP2A/C by RNA interference enhances Bcl2 phosphorylation, suppresses p53-Bcl2 interaction and prolongs cell survival. Purified PP2A can directly enhance the formation of the p53-Bcl2 complex in vitro in an okadaic acid-sensitive manner, supporting a direct mechanism. Importantly, PP2A directly interacts with Bcl2 at its BH4 domain which may function as the PP2A ‘docking site’ to potentially ‘bridge’ PP2A to the flexible loop domain which contains the physiological serine 70 phosphorylation site. Thus, PP2A may provide a double whammy to Bcl2’s survival function by both dephosphorylating and enhancing p53-Bcl2 binding. Therapeutically stimulating Bcl2 dephosphorylation and/or increasing Bcl2/p53 binding by activating PP2A may represent an efficient and novel antineoplastic approach.

scholarly journals Constant expression and activity of protein phosphatase 2A in synchronized cells.

1991 ◽  
Vol 11 (8) ◽  
pp. 4282-4285 ◽  
Author(s):  
R Ruediger ◽  
J E Van Wart Hood ◽  
M Mumby ◽  
G Walter
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Cellular Protein ◽  
Quantitative Comparison ◽  
Resting Cells ◽  
Constant Amount ◽  
Total Cellular Protein ◽  
B Subunit ◽  
Phosphatase 2A ◽  
Constant Expression

The levels of the A, B, and C subunits of protein phosphatase 2A in extracts from synchronized embryonic bovine tracheal cells were determined by immunoblotting with subunit-specific antibodies. A constant amount of each subunit was found in resting cells as well as in growing cells from all stages of the cell cycle. The phosphatase activity of protein phosphatase 2A was also constant. A quantitative comparison showed that the A and C subunits were present in similar amounts, whereas the B subunit was present at a significantly lower level. Together, the A, B, and C subunits represented approximately 0.2% of the total cellular protein.

scholarly journals Mitochondrial Protein Phosphatase 2A Regulates Cell Death Induced by Simulated Ischemia in Kidney NRK-52E Cells

Cell Cycle ◽  
2007 ◽  
Vol 6 (19) ◽  
pp. 2377-2385 ◽  
Author(s):  
Chun Chui Tsao ◽  
Alina Felicia Nica ◽  
Svitlana M. Kurinna ◽  
Tilahun Jiffar ◽  
Marc Mumby ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Mitochondrial Protein ◽  
Simulated Ischemia ◽  
Phosphatase 2A

Constant expression and activity of protein phosphatase 2A in synchronized cells

1991 ◽  
Vol 11 (8) ◽  
pp. 4282-4285
Author(s):  
R Ruediger ◽  
J E Van Wart Hood ◽  
M Mumby ◽  
G Walter
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Cellular Protein ◽  
Quantitative Comparison ◽  
Resting Cells ◽  
Constant Amount ◽  
Total Cellular Protein ◽  
B Subunit ◽  
Phosphatase 2A ◽  
Constant Expression

The levels of the A, B, and C subunits of protein phosphatase 2A in extracts from synchronized embryonic bovine tracheal cells were determined by immunoblotting with subunit-specific antibodies. A constant amount of each subunit was found in resting cells as well as in growing cells from all stages of the cell cycle. The phosphatase activity of protein phosphatase 2A was also constant. A quantitative comparison showed that the A and C subunits were present in similar amounts, whereas the B subunit was present at a significantly lower level. Together, the A, B, and C subunits represented approximately 0.2% of the total cellular protein.

scholarly journals Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

2019 ◽  
Vol 116 (25) ◽  
pp. 12422-12427 ◽  
Author(s):  
Mingzhu Zheng ◽  
Dan Li ◽  
Zhishan Zhao ◽  
Dmytro Shytikov ◽  
Qin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
Cell Survival ◽  
Protein Phosphatase ◽  
Essential Role ◽  
Protein Phosphatase 2A ◽  
Thymocyte Development ◽  
Double Positive ◽  
Phosphatase 2A

The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2caflox/flox-Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4+ CD8+ cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival.

scholarly journals B56-Associated Protein Phosphatase 2A Is Required For Survival and Protects from Apoptosis in Drosophila melanogaster

2002 ◽  
Vol 22 (11) ◽  
pp. 3674-3684 ◽  
Author(s):  
Xinghai Li ◽  
Anne Scuderi ◽  
Anthea Letsou ◽  
David M. Virshup
Keyword(s):  
Cell Death ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Specific Protein ◽  
S2 Cells ◽  
Regulatory Subunits ◽  
Pp2a Activity ◽  
Phosphatase 2A

ABSTRACT Protein phosphorylation and specific protein kinases can initiate signal transduction pathways leading to programmed cell death. The specific protein phosphatases regulating apoptosis have been more elusive. Using double-stranded RNA-mediated interference (RNAi), the role of protein phosphatase 2A (PP2A) in cellular signaling was investigated. Knockdown of A or C subunits individually or of combined B subunits led to concurrent loss of nontargeted PP2A subunits, suggesting that PP2A is an obligate heterotrimer in vivo. Global knockdown of PP2A activity or specific loss of redundant B56 regulatory subunits caused cell death with the morphological and biochemical changes characteristic of apoptosis in cultured S2 cells. B56:PP2A-regulated apoptosis required caspases and the upstream regulators dark, reaper, head involution defective, and dp53. In Drosophila embryos, knockdown of B56-regulated PP2A activity resulted in apoptosis and failure of gastrulation, an effect that was blocked by concurrent RNAi of the caspase Drice. B56-regulated PP2A activity appears to be required upstream of dp53 to maintain a critical proapoptotic substrate in a dephosphorylated, inactive state, thereby preventing apoptosis in Drosophila S2 cells.

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