Isoforms of the promyelocytic leukemia protein differ in their effects on ND10 organization

Beech, Stephanie J.; Lethbridge, Katherine J.; Killick, Neil; McGlincy, Nicholas J.; Leppard, Keith N.

doi:10.1016/j.yexcr.2005.03.012

Cited by 30 publications

(27 citation statements)

References 27 publications

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“…Such cell type and expression level variations could explain differences in PML isoform localisation reported in previous papers (e.g. Beech et al, 2005;Condemine et al, 2007;Condemine et al, 2006). The specifics of these cell type differences are not as important as the general principles that PML isoform behaviour is complicated by many factors, and that individual PML isoforms cannot be relied upon to re-form truly authentic ND10 in a PML-depleted background.…”

Section: Discussionmentioning

confidence: 83%

PML isoforms I and II participate in PML-dependent restriction of HSV-1 replication

Cuchet

Sykes

Nicolas

et al. 2011

Journal of Cell Science

123

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Intrinsic antiviral resistance mediated by constitutively expressed cellular proteins is one arm of defence against virus infection. Promyelocytic leukaemia nuclear bodies (PML-NBs, also known as ND10) contribute to host restriction of herpes simplex virus type 1 (HSV-1) replication via mechanisms that are counteracted by viral regulatory protein ICP0. ND10 assembly is dependent on PML, which comprises several different isoforms, and depletion of all PML isoforms decreases cellular resistance to ICP0-null mutant HSV-1. We report that individual expression of PML isoforms I and II partially reverses the increase in ICP0-null mutant HSV-1 plaque formation that occurs in PML-depleted cells. This activity of PML isoform I is dependent on SUMO modification, its SUMO interaction motif (SIM), and each element of its TRIM domain. Detailed analysis revealed that the punctate foci formed by individual PML isoforms differ subtly from normal ND10 in terms of composition and/or Sp100 modification. Surprisingly, deletion of the SIM motif from PML isoform I resulted in increased colocalisation with other major ND10 components in cells lacking endogenous PML. Our observations suggest that complete functionality of PML is dependent on isoform-specific C-terminal sequences acting in concert.

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Section: Discussionmentioning

confidence: 83%

PML isoforms I and II participate in PML-dependent restriction of HSV-1 replication

Cuchet

Sykes

Nicolas

et al. 2011

Journal of Cell Science

123

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“…It has been proposed that by regulating availability or activity of regulatory factors, PML limits strong signal outputs (18b). Although part of these diverse effects may be mechanistically similar, the PML heterogeneous morphology, composition, and preferential interactions imply distinct functions of the different PML splicing isoforms (3).…”

Section: Discussionmentioning

confidence: 99%

Gamma Interferon-Dependent Transcriptional Memory via Relocalization of a Gene Locus to PML Nuclear Bodies

Gialitakis

Arampatzi

Makatounakis

et al. 2010

Molecular and Cellular Biology

145

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Memory of past cellular responses is an essential adaptation to repeating environmental stimuli. We addressed the question of whether gamma interferon (IFN-␥)-inducible transcription generates memory that sensitizes cells to a second stimulus. We have found that the major histocompatibility complex class II gene DRA is relocated to promyelocytic leukemia (PML) nuclear bodies upon induction with IFN-␥, and this topology is maintained long after transcription shut off. Concurrent interaction of PML protein with mixedlineage leukemia generates a prolonged permissive chromatin state on the DRA gene characterized by high promoter histone H3 K4 dimethylation that facilitates rapid expression upon restimulation. We propose that the primary signal-induced transcription generates spatial and epigenetic memory that is maintained through several cell generations and endows the cell with increased responsiveness to future activation signals.

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“…N-terminally FLAG-tagged PML cDNA clones in pCIneo expressing nuclear isoforms I-VI (Beech et al, 2005), and an Ad5 E4 Orf3 expression plasmid (Hoppe et al, 2006), have been described previously. The PML DRBCC deletion links the N-terminal FLAG epitope to PML residue 361, immediately distal to the RBCC motif.…”

Section: Methodsmentioning

confidence: 99%

Adenovirus type 5 E4 Orf3 protein targets promyelocytic leukaemia (PML) protein nuclear domains for disruption via a sequence in PML isoform II that is predicted as a protein interaction site by bioinformatic analysis

Leppard

Emmott

Cortese

et al. 2009

Journal of General Virology

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Human adenovirus type 5 infection causes the disruption of structures in the cell nucleus termed promyelocytic leukaemia (PML) protein nuclear domains or ND10, which contain the PML protein as a critical component. This disruption is achieved through the action of the viral E4 Orf3 protein, which forms track-like nuclear structures that associate with the PML protein. This association is mediated by a direct interaction of Orf3 with a specific PML isoform, PMLII. We show here that the Orf3 interaction properties of PMLII are conferred by a 40 aa residue segment of the unique C-terminal domain of the protein. This segment was sufficient to confer interaction on a heterologous protein. The analysis was informed by prior application of a bioinformatic tool for the prediction of potential protein interaction sites within unstructured protein sequences (predictors of naturally disordered region analysis; PONDR). This tool predicted three potential molecular recognition elements (MoRE) within the C-terminal domain of PMLII, one of which was found to form the core of the Orf3 interaction site, thus demonstrating the utility of this approach. The sequence of the mapped Orf3-binding site on PML protein was found to be relatively poorly conserved across other species; however, the overall organization of MoREs within unstructured sequence was retained, suggesting the potential for conservation of functional interactions. INTRODUCTIONHuman adenovirus type 5 (Ad5) is one of a diverse collection of viruses that interact during infection with nuclear structures termed ND10 or promyelocytic leukaemia (PML) protein nuclear domains (PML-NDs reviewed by Everett & Chelbi-Alix, 2007;. These structures are complex multiprotein assemblies within which PML is a key component, essential for the localization of other proteins to PML-NDs. PML-NDs have been implicated in a variety of important cell processes, including DNA damage and stress responses, senescence, apoptosis and innate immunity (Bernardi & Pandolfi, 2007).The targeting of PML-NDs by viruses has been linked to avoidance of innate immune responses. The incoming genomes of several nucleus-replicating DNA viruses localize adjacent to PML-NDs (Ishov & Maul, 1996). For herpes simplex virus type 1 (HSV1), this has been shown to involve the mobilization of existing PML-ND components to the sites of virus ingress (Everett & Murray, 2005). Both HSV1 and human cytomegalovirus infections induce the gross disruption of PML-NDs and, for HSV1, degradation of the PML protein (Everett & Maul, 1994;Kelly et al., 1995). Ad5 infection disrupts PML-NDs by deforming them into a large number of elongated tracks (Carvalho et al., 1995; Doucas et al., 1996). For both HSV1 and Ad5, mutations that prevent expression of the virus-coded PML-ND disruption function leave the viruses highly sensitive to innate and intrinsic antiviral responses (Everett et al., 2006(Everett et al., , 2008Ullman & Hearing, 2008;Ullman et al., 2007). Thus it has been proposed that PML-NDs or their components play a key role ...

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Isoforms of the promyelocytic leukemia protein differ in their effects on ND10 organization

Cited by 30 publications

References 27 publications

PML isoforms I and II participate in PML-dependent restriction of HSV-1 replication

PML isoforms I and II participate in PML-dependent restriction of HSV-1 replication

Gamma Interferon-Dependent Transcriptional Memory via Relocalization of a Gene Locus to PML Nuclear Bodies

Adenovirus type 5 E4 Orf3 protein targets promyelocytic leukaemia (PML) protein nuclear domains for disruption via a sequence in PML isoform II that is predicted as a protein interaction site by bioinformatic analysis

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