PP2A Phosphatase as an Emerging Viral Host Factor

Abstract

Protein phosphatase 2A (PP2A) is one of the most ubiquitous cellular proteins and is responsible for the vast majority of Ser/Thr phosphatase activity in eukaryotes. PP2A is a heterotrimer, and its assembly, intracellular localization, enzymatic activity, and substrate specificity are subject to dynamic regulation. Each of its subunits can be targeted by viral proteins to hijack and modulate its activity and downstream signaling to the advantage of the virus. Binding to PP2A is known to be essential to the life cycle of many viruses and seems to play a particularly crucial role for oncogenic viruses, which utilize PP2A to transform infected cells through controlling the cell cycle and apoptosis. Here we summarise the latest developments in the field of PP2A viral targeting; in particular recent discoveries of PP2A hijacking through molecular mimicry of a B56-specific motif by several different viruses. We also discuss the potential as well as shortcomings for therapeutic intervention in the face of our current understanding of viral PP2A targeting.

Pathogen Protein Modularity Enables Elaborate Mimicry of a Host Phosphatase

“…[7][8][9][10][11] Human PP2A is a ubiquitous virulence target by oncogenic viruses, some of which can also bind to the core enzyme. 25 However, these viral proteins mostly inhibit the PP2A enzymatic activity rather than mimicking the function of B subunits. In plants, PP2A has been reported to regulate immunity 26 and associate with the virulence function of the type IIIsecreted effectors AvrE of the bacterial pathogen Pseudomonas syringae and its homolog DspA/E in Erwinia amylovora.…”

Emerging Roles of B56 Phosphorylation and Binding Motif in PP2A-B56 Holoenzyme Biological Function

“…Consequently, targeting specific PP2A-B56 isoforms holds promise as a feasible and valuable therapeutic approach. Many viruses manipulate the activity of PP2A and downstream signaling pathways to their advantage by binding to various component subunits of PP2A, and therefore PP2A is considered a virus-host factor [46][47][48]. The classic example is that the small T antigen (ST) of simian virus 40 (SV40) interacts with the PP2A scaffolding A by displacing regulatory B subunits, thereby inhibiting PP2A-mediated dephosphorylation of numerous substrates and ultimately promoting viral replication [49].…”

Interplay between cellular metabolism and DNA viruses

“…In immunocompromised patients, the viruses remain latent after initial infection 22 . Small T antigen (ST) and large T antigen (LT) play a role in the transformation of infected cells 23 . Several studies with polyomavirus‐transformed cells show that these viruses alter cellular glucose metabolism 24 .…”

“…22 Small T antigen (ST) and large T antigen (LT) play a role in the transformation of infected cells. 23 Several studies with polyomavirus-transformed cells show that these viruses alter cellular glucose metabolism. 24 The protein phosphatase 2A (PP2A) is a critical regulator of the MAPK signaling cascade and has many functions in the control of cellular metabolisms such as glycolysis, lipid metabolism, catecholamine synthesis cycle progression, DNA replication, DNA transcription, protein translation, signal transduction, cytoskeletal dynamics, cell mobility, and apoptosis.…”