Abstract
Components of promyelocytic leukaemia (PML) nuclear bodies (ND10) are recruited to sites associated with herpes simplex virus type 1 (HSV-1) genomes soon after they enter the nucleus. This cellular response is linked to intrinsic antiviral resistance and is counteracted by viral regulatory protein ICP0. We report that the SUMO interaction motifs of PML, Sp100 and hDaxx are required for recruitment of these repressive proteins to HSV-1 induced foci, which also contain SUMO conjugates and PIAS2β, a SUMO E3 ligase. SUMO modification of PML and elements of its tripartite motif (TRIM) are also required for recruitment in cells lacking endogenous PML. Mutants of PML isoform I and hDaxx that are not recruited to virus induced foci are unable to reproduce the repression of ICP0 null mutant HSV-1 infection mediated by their wild type counterparts. We conclude that recruitment of ND10 components to sites associated with HSV-1 genomes reflects a cellular defence against invading pathogen DNA that is regulated through the SUMO modification pathway.
Highlights
Herpesvirus infections are controlled by acquired and innate defences involving cellular, humoral and cytokine mediated responses
A third arm of antiviral defence has been described, named intrinsic immunity or intrinsic resistance, that is conferred by constitutively expressed cellular proteins
In the case of herpesviruses, intrinsic resistance involves the action of cellular repressors that restrict viral transcription once the viral genome enters the nucleus
Summary
Herpesvirus infections are controlled by acquired and innate defences involving cellular, humoral and cytokine mediated responses (for reviews, see [1]). Unlike cytokine-mediated responses, intrinsic antiviral resistance involves the actions of preexisting cellular proteins that, in the case of herpesviruses, act to repress viral transcription [2,3,4]. This defence is counteracted by viral regulatory proteins, for example the immediate-early (IE) proteins ICP0 of herpes simplex virus type 1 (HSV-1) [5,6,7], ie (IE72) of human cytomegalovirus (HCMV) [8], and HCMV virion component pp71 [9,10,11,12,13,14]. ICP0 null mutant HSV-1 exhibits a greatly reduced plaque forming efficiency, but this defect is partially reversed in cells depleted of PML, Sp100, hDaxx or ATRX [5,6,7]
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