PP2A Phosphatase as an Emerging Viral Host Factor

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.

Co-targeting myelin inhibitors and CSPGs enhances sensory axon regeneration within, but not into, the spinal cord

ABSTRACTA major barrier to intraspinal regeneration after dorsal root (DR) injury is the DR entry zone (DREZ), the CNS/PNS interface. DR axons stop regenerating at the DREZ, even if regenerative capacity is increased by a conditioning lesion. This potent blockade has long been attributed to myelin-associated inhibitors and CSPGs, but incomplete lesions and conflicting reports have hampered conclusive agreement. Here we evaluated DR regeneration in adult mice, using novel strategies to facilitate complete lesions and comprehensive analyses, selective tracing of proprio-/mechanoreceptive axons with AAV2, and genetic or viral targeting of Nogo, MAG, OMgp, CSPGs and GDNF. Simultaneously eliminating Nogo/MAG/OMgp elicited little intraspinal penetration of DR axons, even with additional removal of CSPGs and a conditioning lesion. Their absence, however, synergistically enhanced GDNF-elicited intraspinal regeneration. We conclude that myelin inhibitors and CSPGs constrain intraspinal regrowth of DR axons, but that they are not the primary mechanism(s) stopping axons at the DREZ.

Chemogenetic activation of mesoaccumbal Gamma-Aminobutyric Acid projections selectively tunes responses to predictive cues when reward value is abruptly decreased

ABSTRACTBackgroundMesolimbic circuits regulate the attribution of motivational significance to incentive cues that predict reward, yet this network also plays a key role in adapting reward-seeking behavior when the contingencies linked to a cue unexpectedly change. Here we asked whether mesoaccumbal gamma-aminobutyric acid (GABA) projections enhance adaptive responding to incentive cues of abruptly altered reward value, and whether these effects were distinct from global activation of all ventral tegmental area (VTA) GABA circuits.MethodsWe used a viral targeting system to chemogenetically activate mesoaccumbal GABA projections in male rats during a novel cue-dependent operant Value Shifting (VS) task, in which the volume of a sucrose reward associated with a predictive cue is suddenly altered, from the beginning and throughout the session. We compared the results with global activation of VTA GABA neurons, which will activate local inhibitory circuits and long loop projections.ResultsWe found that activation of mesoaccumbal GABA projections decreases responding to incentive cues associated with smaller-than-expected rewards. This tuning of behavioral responses was specific to cues associated with smaller-than-expected rewards, but did not impact measures related to consuming the reward. In marked contrast, activating all VTA(GABA) neurons resulted in a uniform decrease in responding to incentive cues irrespective of changes in the size of the reward.ConclusionsTargeted activation of mesoaccumbal GABA neurons facilitate adaptation in reward-seeking behaviors. This suggests that these projections may play a very specific role in associative learning processes.