Swine Promyelocytic Leukemia Isoform II Inhibits Pseudorabies Virus Infection by Suppressing Viral Gene Transcription in PML-NBs

Abstract

Promyelocytic leukaemia nuclear bodies (PML-NBs) possess an important intrinsic antiviral activity against -herpesvirus infection. PML is the structural backbone of NBs, comprising different isoforms. However, the contribution of each isoform to -herpesvirus restriction is not well understood. Here, we report the role of PML-NBs and swine PML (sPML) isoforms in pseudorabies virus (PRV) infection in its natural host swine cells. We found that sPML-NBs exhibit an anti-PRV activity in the context of increasing the expression level of endogenous sPML. Of four sPML isoforms cloned and examined, only isoform sPML-II/IIa, not sPML-I and IVa, expressed in a sPML knockout cells inhibits PRV infection. Both the unique 7b region of sPML-II and sumoylation-dependent normal formation of PML-NBs are required. 7b possesses a transcriptional repression activity and suppresses viral gene transcription during PRV infection with the cysteine residue 589 and 599 being critically involved. We conclude that sPML-NBs inhibit PRV infection by repressing viral gene transcription through the 7b region of sPML-II. IMPORTANCEPML-NBs are nuclear sites that mediate the antiviral restriction of -herpesvirus gene expression and replication. However, the contrition of each PML isoform to this activity of PML-NBs is not well characterized. Using PRV and its natural host swine cells as a system, we have discovered that the unique C-terminus of sPML isoform II is required for PML-NBs to inhibit PRV infection by directly engaging in repression of viral gene transcription. Our study not only confirms in swine cells that PML-NBs have an anti-viral function, but also presents a mechanism to suggest that PML-NBs inhibit viral infection in an isoform specific manner.