SUMO Pathway Dependent Recruitment of Cellular Repressors to Herpes Simplex Virus Type 1 Genomes

Cuchet-Lourenço, Delphine; Boutell, Chris; Lukashchuk, Vera; Grant, Kyle; Sykes, Amanda; Murray, Jill; Orr, Anne; Everett, Roger D.

doi:10.1371/journal.ppat.1002123

Cited by 95 publications

(140 citation statements)

References 53 publications

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“…A similar phenomenon was observed by Cuchet-Lourenço and colleagues when expressing the PML I 3KR mutant in HFFs. However, the mutation of one further minor SUMOylation site (K616) eliminated all modified bands (49). PML VI lacks the K616 SUMO site; however, four additional minor SUMOylation sites (K226, K380, K497, and K400) were reported for this isoform, which might be SUMOylated under specific conditions in a cell type-specific manner (50,51).…”

Section: Discussionmentioning

confidence: 98%

The Human Cytomegalovirus IE1 Protein Antagonizes PML Nuclear Body-Mediated Intrinsic Immunity via the Inhibition of PML De Novo SUMOylation

Schilling

Scherer

Reuter

et al. 2017

J Virol

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PML nuclear bodies (NBs) are accumulations of cellular proteins embedded in a scaffold-like structure built by SUMO-modified PML/TRIM19. PML and other NB proteins act as cellular restriction factors against human cytomegalovirus (HCMV); however, this intrinsic defense is counteracted by the immediate early protein 1 (IE1) of HCMV. IE1 directly interacts with the PML coiled-coil domain via its globular core region and disrupts NB foci by inducing a loss of PML SUMOylation. Here, we demonstrate that IE1 acts via abrogating the de novo SUMOylation of PML. In order to overcome reversible SUMOylation dynamics, we made use of a cell-based assay that combines inducible IE1 expression with a SUMO mutant resistant to SUMO proteases. Interestingly, we observed that IE1 expression did not affect preSUMOylated PML; however, it clearly prevented de novo SUMO conjugation. Consistent results were obtained by in vitro SUMOylation assays, demonstrating that IE1 alone is sufficient for this effect. Furthermore, IE1 acts in a selective manner, since K160 was identified as the main target lysine. This is strengthened by the fact that IE1 also prevents As 2 O 3 -mediated hyperSUMOylation of K160, thereby blocking PML degradation. Since IE1 did not interfere with coiled-coil-mediated PML dimerization, we propose that IE1 affects PML autoSUMOylation either by directly abrogating PML E3 ligase function or by preventing access to SUMO sites. Thus, our data suggest a novel mechanism for how a viral protein counteracts a cellular restriction factor by selectively preventing the de novo SUMOylation at specific lysine residues without affecting global protein SUMOylation. IMPORTANCEThe human cytomegalovirus IE1 protein acts as an important antagonist of a cellular restriction mechanism that is mediated by subnuclear structures termed PML nuclear bodies. This function of IE1 is required for efficient viral replication and thus constitutes a potential target for antiviral strategies. In this paper, we further elucidate the molecular mechanism for how IE1 antagonizes PML NBs. We show that tight binding of IE1 to PML interferes with the de novo SUMOylation of a distinct lysine residue that is also the target of stress-mediated hyperSUMOylation of PML. This is of importance since it represents a novel mechanism used by a viral antagonist of intrinsic immunity. Furthermore, it highlights the possibility of developing small molecules that specifically abrogate this PML-antagonistic activity of IE1 and thus inhibit viral replication.KEYWORDS PML nuclear bodies, human cytomegalovirus, immediate early 1, intrinsic immunity, nuclear domain 10, sumoylation P romyelocytic leukemia protein (PML) is known to act as organizer of subnuclear, matrix-associated structures which can be detected as spherical dots of approximately 0.1 to 1.0 m (1). These structures, termed PML nuclear bodies (NBs) or nuclear domain 10 (ND10), are multiprotein complexes consisting of more than 160 proteins.

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Section: Discussionmentioning

confidence: 98%

The Human Cytomegalovirus IE1 Protein Antagonizes PML Nuclear Body-Mediated Intrinsic Immunity via the Inhibition of PML De Novo SUMOylation

Schilling

Scherer

Reuter

et al. 2017

J Virol

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“…40). Often in their sumoylated forms, some partners have been implicated in IFN effects on senescence (DAXX, p53, SP100) or antiviral defence (SP100) [41][42][43][44][45][46] . These unexpected findings therefore point to the existence of a highly integrated regulatory loop wherein the substrates, their modifiers (SUMOs) and the catalyser (PML NBs) are all dramatically upregulated during IFN response, promoting the rapid formation of the active, SUMO-conjugated form.…”

Section: Discussionmentioning

confidence: 99%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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Small ubiquitin-related modifier (SUMO) protein conjugation onto target proteins regulates multiple cellular functions, including defence against pathogens, stemness and senescence. SUMO1 peptides are limiting in quantity and are thus mainly conjugated to high-affinity targets. Conjugation of SUMO2/3 paralogues is primarily stress inducible and may initiate target degradation. Here we demonstrate that the expression of SUMO1/2/3 is dramatically enhanced by interferons through an miRNA-based mechanism involving the Lin28/let-7 axis, a master regulator of stemness. Normal haematopoietic progenitors indeed display much higher SUMO contents than their differentiated progeny. Critically, SUMOs contribute to the antiviral effects of interferons against HSV1 or HIV. Promyelocytic leukemia (PML) nuclear bodies are interferon-induced domains, which facilitate sumoylation of a subset of targets. Our findings thus identify an integrated interferon-responsive PML/SUMO pathway that impedes viral replication by enhancing SUMO conjugation and possibly also modifying the repertoire of targets. Interferon-enhanced post-translational modifications may be essential for senescence or stem cell self-renewal, and initiate SUMO-dependent proteolysis.

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“…The process occurs extremely rapidly and does not depend on expression of viral protein, implying an intrinsic antiviral response to viral genome entry (Everett and Murray, 2005). The SUMO interaction motifs of PML, Sp100 and hDaxx are necessary for recruitment of these repressive proteins to HSV-1 genomes (Cuchet-Lourenço et al, 2011).…”

Section: Association Of Pml Nbs With the Viral Genomes Contributes Tomentioning

confidence: 99%

“…Recruitment of PML NBs components to sites associated with HSV-1 genomes and VZV nucleocapsids contributes to the intrinsic defense against invading viral genome Cuchet-Lourenço et al, 2011;Reichelt et al, 2011), which suggests a crucial role of PML NBs in resistance to viral infection. However, the association of PML NBs with viral genome is complex in nature and requires further study.…”

Section: Association Of Pml Nbs With the Viral Genomes Contributes Tomentioning

confidence: 99%

The potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1

2012

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Herpes simplex virus type 1 (HSV-1) is a common human pathogen causing cold sores and even more serious diseases. It can establish a latent stage in sensory ganglia after primary epithelial infections, and reactivate in response to stress or sunlight. Previous studies have demonstrated that viral immediate-early protein ICP0 plays a key role in regulating the balance between lytic and latent infection. Recently, It has been determined that promyelocytic leukemia (PML) nuclear bodies (NBs), small nuclear sub-structures, contribute to the repression of HSV-1 infection in the absence of functional ICP0. In this review, we discuss the fundamentals of the interaction between ICP0 and PML NBs, suggesting a potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1.

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SUMO Pathway Dependent Recruitment of Cellular Repressors to Herpes Simplex Virus Type 1 Genomes

Cited by 95 publications

References 53 publications

The Human Cytomegalovirus IE1 Protein Antagonizes PML Nuclear Body-Mediated Intrinsic Immunity via the Inhibition of PML De Novo SUMOylation

The Human Cytomegalovirus IE1 Protein Antagonizes PML Nuclear Body-Mediated Intrinsic Immunity via the Inhibition of PML De Novo SUMOylation

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

The potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1

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