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Published on: April 23, 2012
Down-regulation of Na/K+ atpase activity by human parvovirus B19 capsid protein VP1
Ahmad Almilaji1, Kalina Szteyn, Evelyn Fein
1Department of Physiology, University of Tübingen, Tübingen, Germany.
Background/Aims:
Human parvovirus B19 (B19V) may cause inflammatory cardiomyopathy (iCMP) which is accompanied by endothelial dysfunction. The B19V capsid protein VP1 contains a lysophosphatidylcholine producing phospholipase A2 (PLA) sequence. Lysophosphatidylcholine has in turn been shown to inhibit Na(+)/K(+) ATPase. The present study explored whether VP1 modifies Na(+)/K(+) ATPase activity.
Methods:
Xenopus oocytes were injected with cRNA encoding VP1 isolated from a patient suffering from fatal B19V-iCMP or cRNA encoding PLA2-negative VP1 mutant (H153A) and K(+) induced pump current (I(pump)) as well as ouabain-inhibited current (I(ouabain)) both reflecting Na(+)/K(+)-ATPase activity were determined by dual electrode voltage clamp.
Results:
Injection of cRNA encoding VP1, but not of VP1(H153A) or water, was followed by a significant decrease of both, I(pump) and I(ouabain) in Xenopus oocytes. The effect was not modified by inhibition of transcription with actinomycin (10 µM for 36 hours) but was abrogated in the presence of PLA2 specific blocker 4-bromophenacylbromide (50 µM) and was mimicked by lysophosphatidylcholine (0.5 - 1 µg/ml). According to whole cell patch clamp, lysophosphatidylcholine (1 µg /ml) similarly decreased I(pump) in human microvascular endothelial cells (HMEC).
Conclusion:
The B19V capsid protein VP1 is a powerful inhibitor of host cell Na(+)/K(+) ATPase, an effect at least partially due to phospholipase A2 (PLA2) dependent formation of lysophosphatidylcholine.
Insights
Human parvovirus B19 capsid protein VP1 inhibits Na+/K+ ATPase activity. This inhibition is partly due to phospholipase A2 (PLA2) producing lysophosphatidylcholine, impacting host cell function.
Area of Science:
- Virology
- Molecular Biology
- Cardiology
Background:
- Human parvovirus B19 (B19V) is linked to inflammatory cardiomyopathy (iCMP) and endothelial dysfunction.
- The B19V capsid protein VP1 possesses a phospholipase A2 (PLA2) domain capable of producing lysophosphatidylcholine.
- Lysophosphatidylcholine is known to inhibit the Na+/K+ ATPase, a critical ion pump in cell function.
Purpose of the Study:
- To investigate whether the B19V VP1 protein directly modulates Na+/K+ ATPase activity.
- To determine the role of the VP1 protein's PLA2 activity in Na+/K+ ATPase inhibition.
Main Methods:
- Xenopus oocytes were injected with cRNA encoding wild-type VP1 or a PLA2-inactive mutant (VP1 H153A).
- Na+/K+ ATPase activity was assessed by measuring K+ induced pump current (Ipump) and ouabain-inhibited current (Iouabain) using dual electrode voltage clamp.
- Whole-cell patch clamp was used to evaluate the effect of lysophosphatidylcholine on Na+/K+ ATPase in human microvascular endothelial cells (HMEC).
Main Results:
- Injection of wild-type VP1 cRNA significantly decreased both Ipump and Iouabain in Xenopus oocytes, while the VP1 H153A mutant had no effect.
- The inhibitory effect of VP1 was abrogated by a PLA2-specific blocker and mimicked by exogenous lysophosphatidylcholine.
- Lysophosphatidylcholine also reduced Ipump in human microvascular endothelial cells, confirming its inhibitory action on Na+/K+ ATPase.
Conclusions:
- The B19V capsid protein VP1 acts as a potent inhibitor of host cell Na+/K+ ATPase.
- This inhibition is, at least partially, mediated by the PLA2-dependent generation of lysophosphatidylcholine.
- These findings provide a molecular mechanism linking B19V infection to cellular dysfunction in iCMP.
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