pUL21 is a viral phosphatase adaptor that promotes herpes simplex virus replication and spread

Abstract

The herpes simplex virus (HSV)-1 protein pUL21 is essential for efficient virus replication and dissemination. While pUL21 has been shown to promote multiple steps of virus assembly and spread, the molecular basis of its function remained unclear. Here we identify that pUL21 is a virus-encoded adaptor of protein phosphatase 1 (PP1). pUL21 directs the dephosphorylation of cellular and virus proteins, including components of the viral nuclear egress complex, and we define a conserved non-canonical linear motif in pUL21 that is essential for PP1 recruitment. In vitro evolution experiments reveal that pUL21 directly antagonises the activity of the virus-encoded kinase pUS3, with growth and spread of pUL21 PP1-binding mutant viruses being restored when pUS3 activity is disrupted. This study shows that virus-directed phosphatase activity is essential for efficient herpesvirus assembly and spread, highlighting the fine balance between kinase and phosphatase activity required for optimal virus replication.

pUL21 regulation of pUs3 Kinase Activity Influences the Nature of Nuclear Envelope Deformation by the HSV-2 Nuclear Egress Complex

“…An alternative explanation for the hyperphosphorylation of pUs3, pUL31 and pUL34 in ΔUL21 infected cells is that pUL21 may promote their dephosphorylation (Figure 9B). This idea is strongly supported by a recent unpublished study from Graham and co-workers that demonstrated HSV-1 pUL21 is an adaptor protein for protein phosphatase 1 (PP1) and furthermore that pUL21 has a penchant for delivery of PP1 to pUs3 substrates to mediate their dephosphorlyation [36]. The fact that pUL21 and pUs3 are only found in members of the Alphaherpesvirinae raises the intriguing possibility that pUL21 exists, in part, to specifically counter the activities of pUs3.…”