Dysregulation of the MEK/ERK/MNK1 signaling cascade by middle T antigen of the trichoydsplasia spinulosa polyomavirus

Abstract

Background

Trichodysplasia spinulosa (TS) is a disfiguring folliculocentric cutaneous disease caused by infection with the trichodysplasia spinulosa polyomavirus (TSPyV). The TSPyV genome contains splice variants encoding the middle tumor (mT) antigen, although the potential role for TSPyV mT antigen in disease development remains unknown.

Objective

The current study was designed to investigate the mechanistic properties of TSPyV mT antigen, which may further our understanding of TS pathogenesis and provide insight into potential therapies.

Methods

A lentiviral packaging system was used to create an inducible cell line expressing TSPyV mT antigen. Proteins were extracted, separated by SDS-PAGE, and subjected to Western blot analysis. Co-immunoprecipitation experiments and mutational analyses were also performed to evaluate protein-protein interactions of mT antigen.

Results

We describe a novel mechanism of action for mT antigen that involves hyperactivation of MEK, ERK, and MNK1. Our findings suggest that dysregulation of these key signaling molecules depends upon TSPyV mT antigen interaction with protein phosphatase 2A (PP2A) via intact Zn binding motifs.

Conclusion

Given that PP2A interaction and MEK/ERK/MNK1 phosphorylation are associated with high levels of cell proliferation and inflammation, our findings provide new evidence that TSPyV mT antigen may contribute to the pro-proliferative conditions that lead to TS development.

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