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Role of Promyelocytic Leukemia Protein in Host Antiviral Defense
Abstract and Figures
Several pathways have been implicated in the establishment of antiviral state in response to interferon (IFN), one of which implicates the promyelocytic leukemia (PML) protein. The PML gene has been discovered 20 years ago and has led to new insights into oncogenesis, apoptosis, cell senescence, and antiviral defense. PML is induced by IFN, leading to a marked increase of expression of PML isoforms and the number of PML nuclear bodies (NBs). PML is the organizer of the NBs that contains at least 2 permanent NB-associated proteins, the IFN-stimulated gene product Speckled protein of 100 kDa (Sp100) and death-associated dead protein (Daxx), as well as numerous other transient proteins recruited in these structures in response to different stimuli. Accumulating reports have implicated PML in host antiviral defense and revealed various strategies developed by viruses to disrupt PML NBs. This review will focus on the regulation of PML and the implication of PML NBs in conferring resistance to DNA and RNA viruses. The role of PML in mediating an IFN-induced antiviral state will also be discussed.
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... Upon HSV-1 infection, the incoming viral genome must encounter waves of host anti-viral defenses while the virus attempts to establish efficient transcription/replication. One of the major anti-viral responses comes from nuclear domain 10 (ND10s). ND10s, also known as promyelocytic leukemia nuclear bodies (PML-NBs), are dynamic nuclear structures involved in numerous cellular functions, such as gene regulation, cell-cycle regulation, apoptosis, and antiviral defenses [7][8][9]. To date, more than 150 proteins have been identified as ND10 components. ...
... To date, more than 150 proteins have been identified as ND10 components. Among them, some are permanent residents, such as promyelocytic leukemia (PML) protein and speckled protein 100 kDa (Sp100), while many others are transient components recruited to ND10 upon stimulations [9,10]. The anti-viral effects of ND10 are reflected in the facts that the size and number of ND10 increase with interferon treatment but diminish in virus infections [11,12]. ...
... ND10 nuclear bodies are dynamic nuclear structures involved in many cellular functions, including gene regulation, cell cycle regulation, and anti-viral responses (7)(8)(9)(10). PML is the main organizer of ND10 that sustains the ND10 structure and recruits ND10 clients via SUMO-SIM interactions [7]. ...
Upon viral entry, components of ND10 nuclear bodies converge with incoming DNA to repress viral expression. The infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) contains a RING-type E3 ubiquitin ligase that targets the ND10 organizer, PML, for proteasomal degradation. Consequently, ND10 components are dispersed and viral genes are activated. Previously, we reported that ICP0 E3 differentiates two similar substrates, PML isoforms I and II, and demonstrated that SUMO-interaction has profound regulatory effects on PML II degradation. In the present study, we investigated elements that regulate the PML I degradation and found that: (i) two regions of ICP0 flanking the RING redundantly facilitate the degradation of PML I; (ii) downstream of the RING, the SUMO-interaction motif located at residues 362-364 (SIM362-364) targets the SUMOylated PML I in the same manner as that of PML II; (iii) upstream of the RING, the N-terminal residues 1-83 mediate PML I degradation regardless of its SUMOylation status or subcellular localization; (iv) the reposition of residues 1-83 to downstream of the RING does not affect its function in PML I degradation; and (v) the deletion of 1-83 allows the resurgence of PML I and reformation of ND10-like structures late in HSV-1 infection. Taken together, we identified a novel substrate recognition specific for PML I, by which ICP0 E3 enforces a continuous PML I degradation throughout the infection to prevent the ND10 reformation.
... Regarding antimicrobial ISG, they can be subdivided into effectors and regulatory genes. Effectors genes codify restriction factors that act directly targeting pathogens, examples are 2 -5 oligo-A synthetase (OAS), which induces viral RNA degradation; Protein Kinase R (PKR) acts by inhibiting viral protein synthesis; Promyelocytic leukemia (PML) protein, the component of PML Nuclear Bodies involved in DNA viruses and retrovirus restriction [34]; Tetherin/BST-2 inhibiting envelope virus release; ISG-15, a ubiquitin-like modifier induced by type I and III IFN, that can be also secreted by the cell and binds the LFA-1 integrin receptor on NK-and T-cells to potentiate their production of type II IFN [35]. OAS and PKR are allosteric enzymes that require activation by dsRNA detection. ...
... PLpro also mediates DAXX re-localization to cytoplasmic sites and promotes its proteasomal degradation [132]. DAXX is a scaffold protein residing in PML nuclear bodies and is able to limit SARS-CoV-2 replication [34]. ...
Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and tropism to promote the adaptive immune response. Type I IFNs induce a systemic response that impacts nearly every cell in the host, while type III IFNs’ susceptibility is restricted to anatomic barriers and selected immune cells. Both IFN types are critical cytokines for the antiviral response against epithelium-tropic viruses being effectors of innate immunity and regulators of the development of the adaptive immune response. Indeed, the innate antiviral immune response is essential to limit virus replication at the early stages of infection, thus reducing viral spread and pathogenesis. However, many animal viruses have evolved strategies to evade the antiviral immune response. The Coronaviridae are viruses with the largest genome among the RNA viruses. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic. The virus has evolved numerous strategies to contrast the IFN system immunity. We intend to describe the virus-mediated evasion of the IFN responses by going through the main phases: First, the molecular mechanisms involved; second, the role of the genetic background of IFN production during SARS-CoV-2 infection; and third, the potential novel approaches to contrast viral pathogenesis by restoring endogenous type I and III IFNs production and sensitivity at the sites of infection.
... The promyelocytic leukemia (PML) gene was initially discovered as the oncogenic fusion partner of RAR␣ in a translocation event that causes acute promyelocytic leukemia (1,2). In mammals, the PML protein forms a subnuclear organelle known as the PML nuclear body (NB) (1-3) that plays a prominent role in antiviral immunity and is a hub for the association and post-translational modification of over 150 proteins involved in transcriptional regulation, replication, and repair of DNA (3)(4)(5). PML is believed to contribute to tumour suppression through several mechanisms including the modulation of innate immune pathways as well as the regulation of the PTEN-AKT-mTOR signaling axis (3,(6)(7)(8)(9). ...
... Thus, the three protein families (PML, Plex9 and TREX) share an important function in maintaining genome integrity in jawed vertebrates by repressing LINE-1 propagation. evolution, which is consistent with the broader role of PML in antiviral innate immune pathways (3,4). ...
We have uncovered a role for the promyelocytic leukemia (PML) gene and novel PML-like DEDDh exonucleases in the maintenance of genome stability through the restriction of LINE-1 (L1) retrotransposition in jawed vertebrates. Although the mammalian PML protein forms nuclear bodies, we found that the spotted gar PML ortholog and related proteins in fish function as cytoplasmic DEDDh exonucleases. In contrast, PML proteins from amniote species localized both to the cytoplasm and formed nuclear bodies. We also identified the PML-like exon 9 (Plex9) genes in teleost fishes that encode exonucleases. Plex9 proteins resemble TREX1 but are unique from the TREX family and share homology to gar PML. We also characterized the molecular evolution of TREX1 and the first non-mammalian TREX1 homologs in axolotl. In an example of convergent evolution and akin to TREX1, gar PML and zebrafish Plex9 proteins suppressed L1 retrotransposition and could complement TREX1 knockout in mammalian cells. Following export to the cytoplasm, the human PML-I isoform also restricted L1 through its conserved C-terminus by enhancing ORF1p degradation through the ubiquitin-proteasome system. Thus, PML first emerged as a cytoplasmic suppressor of retroelements, and this function is retained in amniotes despite its new role in the assembly of nuclear bodies.
... TRIM proteins regulate antiviral signaling pathways and have roles in intrinsic resistance to DNA and RNA virus infections [48,49]. PML/TRIM19, alone or in conjunction with other proteins in PML nuclear bodies, is a well-known restriction factor for several viruses [50][51][52]. TRIM24, TRIM28 and TRIM33 belong to a subfamily of TRIM proteins (TIF1 family) that associate with chromatin through their PHD-bromo domains, regulate gene transcription and have E3 ubiquitin ligase activity [53]. All three also have roles in regulating viral infections. ...
SUMO modifications regulate the function of many proteins and are important in controlling herpesvirus infections. We performed a site-specific proteomic analysis of SUMO1- and SUMO2-modified proteins in Epstein-Barr virus (EBV) latent and lytic infection to identify proteins that change in SUMO modification status in response to EBV reactivation. Major changes were identified in all three components of the TRIM24/TRIM28/TRIM33 complex, with TRIM24 being rapidly degraded and TRIM33 being phosphorylated and SUMOylated in response to EBV lytic infection. Further experiments revealed TRIM24 and TRIM33 repress expression of the EBV BZLF1 lytic switch gene, suppressing EBV reactivation. However, BZLF1 was shown to interact with TRIM24 and TRIM33, resulting in disruption of TRIM24/TRIM28/TRIM33 complexes, degradation of TRIM24 and modification followed by degradation of TRIM33. Therefore, we have identified TRIM24 and TRIM33 as cellular antiviral defence factors against EBV lytic infection and established the mechanism by which BZLF1 disables this defence.
... PML transcription is also induced by IFN type I and II (Stadler et al., 1995; Fig. 1). PML plays a significant role in antiviral responses (Geoffroy and Chelbi-Alix, 2011;Patra and Müller, 2021) through both a direct interference with replication of multiple viruses, but also by enhancing global IFN response through enhancement of STAT1 signaling (Scherer and Stamminger, 2016). Interestingly, several PML NB client proteins are also IFN-inducible and modulate antiviral responses, including Sp100, Daxx, or SUMO (Grötzinger et al., 1996;Sahin et al., 2014a). ...
PML assembles into nuclear domains that have attracted considerable attention from cell and cancer biologists. Upon stress, PML nuclear bodies modulate sumoylation and other post-translational modifications, providing an integrated molecular framework for the multiple roles of PML in apoptosis, senescence, or metabolism. PML is both a sensor and an effector of oxidative stress. Emerging data has demonstrated its key role in promoting therapy response in several hematological malignancies. While these membrane-less nuclear hubs can enforce efficient cancer cell clearance, their downstream pathways deserve better characterization. PML NBs are druggable and their known modulators may have broader clinical utilities than initially thought.
... For example, type I/II interferons (IFNs) enhance the expression of the PML gene, thereby increasing the number and size of PML NBs. Other regulators of PML include the p53 tumor suppressor protein, p73 (the structural homolog of p53) and pro-inflammatory cytokines, summarized in [12,71,72]. To illustrate some of the PML regulation processes the proapoptotic autoregulatory feedback loop between p73, YAP (Yes-associated protein, the transcriptional coactivator) and the PML should be mentioned. ...
Promyelocytic leukemia nuclear bodies (PM NBs), often referred to as membraneless organelles, are dynamic macromolecular protein complexes composed of a PML protein core and other transient or permanent components. PML NBs have been shown to play a role in a wide variety of cellular processes. This review describes in detail the diverse and complex interactions between small and medium size DNA viruses and PML NBs that have been described to date. The PML NB components that interact with small and medium size DNA viruses include PML protein isoforms, ATRX/Daxx, Sp100, Sp110, HP1, and p53, among others. Interaction between viruses and components of these NBs can result in different outcomes, such as influencing viral genome expression and/or replication or impacting IFN-mediated or apoptotic cell responses to viral infection. We discuss how PML NB components abrogate the ability of adenoviruses or Hepatitis B virus to transcribe and/or replicate their genomes and how papillomaviruses use PML NBs and their components to promote their propagation. Interactions between polyomaviruses and PML NBs that are poorly understood but nevertheless suggest that the NBs can serve as scaffolds for viral replication or assembly are also presented. Furthermore, complex interactions between the HBx protein of hepadnaviruses and several PML NBs-associated proteins are also described. Finally, current but scarce information regarding the interactions of VP3/apoptin of the avian anellovirus with PML NBs is provided. Despite the considerable number of studies that have investigated the functions of the PML NBs in the context of viral infection, gaps in our understanding of the fine interactions between viruses and the very dynamic PML NBs remain. The complexity of the bodies is undoubtedly a great challenge that needs to be further addressed.
The key to a curative treatment of hepatitis B virus (HBV) infection is the eradication of the intranuclear episomal covalently closed circular DNA (cccDNA), the stable persistence reservoir of HBV. Currently, established therapies can only limit HBV replication but fail to tackle the cccDNA. Thus, novel therapeutic approaches toward curative treatment are urgently needed. Recent publications indicated a strong association between the HBV core protein SUMOylation and the association with promyelocytic leukemia nuclear bodies (PML-NBs) on relaxed circular DNA to cccDNA conversion. We propose that interference with the cellular SUMOylation system and PML-NB integrity using arsenic trioxide provides a useful tool in the treatment of HBV infection. Our study showed a significant reduction in HBV-infected cells, core protein levels, HBV mRNA, and total DNA. Additionally, a reduction, albeit to a limited extent, of HBV cccDNA could be observed. Furthermore, this interference was also applied for the treatment of an established HBV infection, characterized by a stably present nuclear pool of cccDNA. Arsenic trioxide (ATO) treatment not only changed the amount of expressed HBV core protein but also induced a distinct relocalization to an extranuclear phenotype during infection. Moreover, ATO treatment resulted in the redistribution of transfected HBV core protein away from PML-NBs, a phenotype similar to that previously observed with SUMOylation-deficient HBV core. Taken together, these findings revealed the inhibition of HBV replication by ATO treatment during several steps of the viral replication cycle, including viral entry into the nucleus as well as cccDNA formation and maintenance. We propose ATO as a novel prospective treatment option for further pre-clinical and clinical studies against HBV infection.
IMPORTANCE
The main challenge for the achievement of a functional cure for hepatitis B virus (HBV) is the covalently closed circular DNA (cccDNA), the highly stable persistence reservoir of HBV, which is maintained by further rounds of infection with newly generated progeny viruses or by intracellular recycling of mature nucleocapsids. Eradication of the cccDNA is considered to be the holy grail for HBV curative treatment; however, current therapeutic approaches fail to directly tackle this HBV persistence reservoir. The molecular effect of arsenic trioxide (ATO) on HBV infection, protein expression, and cccDNA formation and maintenance, however, has not been characterized and understood until now. In this study, we reveal ATO treatment as a novel and innovative therapeutic approach against HBV infections, repressing viral gene expression and replication as well as the stable cccDNA pool at low micromolar concentrations by affecting the cellular function of promyelocytic leukemia nuclear bodies.
Genome-wide association studies (GWASs) have identified thousands of non-coding variants that are associated with human complex traits and diseases. The analysis of such GWAS variants in different contexts and physiological states is essential for deciphering the regulatory mechanisms underlying human disease. Alternative polyadenylation (APA) is a key post-transcriptional modification for most human genes that substantially impacts upon cell behavior. Here, we mapped 9,493 3′-untranslated region APA quantitative trait loci in 18 human immune baseline cell types and 8 stimulation conditions (immune 3′aQTLs). Through the comparison between baseline and stimulation data, we observed the high responsiveness of 3′aQTLs to immune stimulation (response 3′aQTLs). Co-localization and mendelian randomization analyses of immune 3′aQTLs identified 678 genes where 3′aQTL are associated with variation in complex traits, 27.3% of which were derived from response 3′aQTLs. Overall, these analyses reveal the role of immune 3′aQTLs in the determination of complex traits, providing new insights into the regulatory mechanisms underlying disease etiologies.
The Influenza A virus is a continuous threat to public health that causes yearly epidemics with the ever-present threat of the virus becoming the next pandemic. Due to increasing levels of resistance, several of our previously used antivirals have been rendered useless. There is a strong need for new antivirals that are less likely to be susceptible to mutations. One strategy to achieve this goal is structure-based drug development. By understanding the minute details of protein structure, we can develop antivirals that target the most conserved, crucial regions to yield the highest chances of long-lasting success. One promising IAV target is the virulence protein non-structural protein 1 (NS1). NS1 contributes to pathogenicity through interactions with numerous host proteins, and many of the resulting complexes have been shown to be crucial for virulence. In this review, we cover the NS1-host protein complexes that have been structurally characterized to date. By bringing these structures together in one place, we aim to highlight the strength of this field for drug discovery along with the gaps that remain to be filled.
Infectious diseases continue to represent a major threat to the humankind. This is reiterated by the current COVID-19 pandemic that affected almost 550 million people worldwide and caused more than 6.35 million deaths. It is clear that in addition to the existing preventive measures and treatments for various pathogens, better understanding is needed of the relationship between pathogen infection and the human antiinfection immune response and of the specific mechanisms underlying these complex processes. There is a constant warfare between the hosts and infectious pathogens, where humans have evolved a very effective and broadly amended antiinfection immune system, but, in their turn, pathogens have evolved a multitude of immune escape mechanisms to efficiently oppose it. It is recognized now that liquid–liquid phase separation (LLPS) occupies a special place among the important molecular mechanisms of the antiinfection immune response. Some illustrative examples of the roles of LLPS in the antiinfection immune response are considered in this chapter.
Nuclear domains called ND10 or PML bodies might function as nuclear depots by recruiting or releasing certain proteins. Although recruitment of proteins through interferon-induced upregulation and SUMO-1 modification level of PML had been defined, it is not known whether release of proteins is regulated and has physiological consequences. Exposure to sublethal environmental stress revealed a sequential release of ND10-associated proteins. Upon heat shock Daxx and Sp100 were released but PML remained, whereas exposure to subtoxic concentrations of CdCl2 induced the release of ND10-associated proteins, including PML, with Sp100 remaining in a few sites. In both cases, recovery times were similar and were followed by a burst of mitotic activity. Cadmium-induced release of proteins from ND10 could be blocked by inhibiting activation of p38 MAPK or ERK1/2. By contrast, heat-shock-induced desumolation of PML and release of proteins from ND10 are unaffected by these inhibitors but can be recapitulated by overexpression of the SUMO isopeptidase SENP-1. Therefore, activation of SENP-1-like SUMO isopeptidase(s) during heat shock is not affected by these kinases. Thus, the release of ND10-associated proteins is not due to a general dispersal of nuclear domains but seems to be regulated by rapid desumolation during thermal stress and through the phosphorylation cascade of stress and mitogenic signaling pathways in the case of CdCl2. Whether the release of certain proteins had consequences was tested for heat-shock-protein transcription and synthesis. Release of Daxx correlated with Hsp25 suppression, suggesting that Daxx normally inhibits immediate Hsp25 production. Release of PML correlated with lower production of Hsp70. These results suggest that segregation or release of PML or Daxx have differential physiological relevance during the stress response. The fact that enzymatic activation of protein release or segregation after stress modifies the heat-shock response strengthens the concept of ND10 as a regulated depot of effector proteins.
Swift elimination of undesirable cells is an important feature in tumour suppression and immunity. The tumour suppressor p53 and interferon- and - (IFN-/) are essential for the induction of apoptosis in cancerous cells and in antiviral immune responses, respectively, but little is known about their interrelationship. Here we show that transcription of the p53 gene is induced by IFN-/, accompanied by an increase in p53 protein level. IFN-/ signalling itself does not activate p53; rather, it contributes to boosting p53 responses to stress signals. We show examples in which p53 gene induction by IFN-/ contributes to tumour suppression. Furthermore, we show that p53 is activated in virally infected cells to evoke an apoptotic response and that p53 is critical for antiviral defence of the host. Our study reveals a hitherto unrecognized link between p53 and IFN-/ in tumour suppression and antiviral immunity, which may have therapeutic implications.
Analyzing the pathways by which retinoic acid (RA) induces promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) catabolism in acute promyelocytic leukemia (APL), we found that, in addition to caspase-mediated PML/RARalpha cleavage, RA triggers degradation of both PML/RARalpha and RARalpha. Similarly, in non-APL cells, RA directly targeted RARalpha and RARalpha fusions to the proteasome degradation pathway. Activation of either RARalpha or RXRalpha by specific agonists induced degradation of both proteins. Conversely, a mutation in RARalpha that abolishes heterodimer formation and DNA binding, blocked both RARalpha and RXRalpha degradation. Mutations in the RARalpha DNA-binding domain or AF-2 transcriptional activation region also impaired RARalpha catabolism. Hence, our results link transcriptional activation to receptor catabolism and suggest that transcriptional up-regulation of nuclear receptors by their ligands may be a feedback mechanism allowing sustained target-gene activation.
The promyelocytic leukemia (PML) protein is expressed in the diffuse nuclear fraction of the nucleoplasm and in matrix-associated structures, known as nuclear bodies (NBs). PML NB formation requires the covalent modification of PML to SUMO. The noncovalent interactions of SUMO with PML based on the identification of a SUMO-interacting motif within PML seem to be required for further recruitment within PML NBs of SUMOylated proteins. RNA viruses whose replication takes place in the cytoplasm and is inhibited by PML have developed various strategies to counteract the antiviral defense mediated by PML NBs. We show here that primary fibroblasts derived from PML knockout mice are more sensitive to infection with encephalomyocarditis virus (EMCV), suggesting that the absence of PML results in an increase in EMCV replication. Also, we found that EMCV induces a decrease in PML protein levels both in interferon-treated cells and in PMLIII-expressing cells. Reduction of PML was carried out by the EMCV 3C protease. Indeed, at early times postinfection, EMCV induced PML transfer from the nucleoplasm to the nuclear matrix and PML conjugation to SUMO-1, SUMO-2, and SUMO-3, leading to an increase in PML body size where the viral protease 3C and the proteasome component were found colocalizing with PML within the NBs. This process was followed by PML degradation occurring in a proteasome- and SUMO-dependent manner and did not involve the SUMO-interacting motif of PML. Together, these findings reveal a new mechanism evolved by EMCV to antagonize the PML pathway in the interferon-induced antiviral defense.
Various reports implicate PML and PML nuclear bodies (NBs) in an intrinsic antiviral response targeting diverse cytoplasmic
replicating RNA viruses. PML conjugation to the small ubiquitin-like modifier (SUMO) is required for its localization within
NBs. PML displays antiviral effects in vivo, as PML deficiency renders mice more susceptible to infection with the rhabdovirus vesicular stomatitis virus (VSV). Cells
derived from these mice are also more sensitive to infection with rabies virus, another member of the rhabdovirus family.
Alternative splicing from a single gene results in the synthesis of several PML isoforms, and these are classified into seven
groups, designated PMLI to -VII. We report here that expression of PMLIV or PMLIVa, which is missing exon 5, inhibited viral
mRNA and protein synthesis, leading to a reduction in viral replication. However, the expression of other nuclear isoforms
(PMLI to -VI) and cytoplasmic PMLVIIb failed to impair viral production. This antiviral effect required PMLIV SUMOylation,
as it was not observed with PMLIV 3KR, in which the lysines involved in SUMO conjugation were mutated. Thus, PMLIV and PMLIVa
may exert this isoform-specific function through interaction with specific NB protein partners via their common C-terminal
region.
The death-associated protein Daxx found in PML (promyelocytic leukemia protein) nuclear bodies (PML-NBs) is involved in transcriptional
regulation and cellular intrinsic antiviral resistence against incoming viruses. We found that knockdown of Daxx in a nontransformed
human hepatocyte cell line using RNA interference (RNAi) techniques results in significantly increased adenoviral (Ad) replication,
including enhanced viral mRNA synthesis and viral protein expression. This Daxx restriction imposed upon adenovirus growth
is counteracted by early protein E1B-55K (early region 1B 55-kDa protein), a multifunctional regulator of cell-cycle-independent
Ad5 replication. The viral protein binds to Daxx and induces its degradation through a proteasome-dependent pathway. We show
that this process is independent of Ad E4orf6 (early region 4 open reading frame 6), known to promote the proteasomal degradation
of cellular p53, Mre11, DNA ligase IV, and integrin α3 in combination with E1B-55K. These results illustrate the importance
of the PML-NB-associated factor Daxx in virus growth restriction and suggest that E1B-55K antagonizes innate antiviral activities
of Daxx and PML-NBs to stimulate viral replication at a posttranslational level.
The mammalian cell nucleus contains a variety of organelles or nuclear bodies which contribute to key nuclear functions. Promyelocytic leukemia nuclear bodies (PML NBs) are involved in the regulation of apoptosis, antiviral responses, the DNA damage response and chromatin structure, but their precise biochemical function in these nuclear pathways is unknown. One strategy to tackle this problem is to assess the biophysical properties of the component parts of these macromolecular assemblies in living cells. In this study we determined PML NB assembly dynamics by live cell imaging, combined with mathematical modeling. For the first time, dynamics of PML body formation were measured in cells lacking endogenous PML. We show that all six human nuclear PML isoforms are able to form nuclear bodies in PML negative cells. All isoforms exhibit individual exchange rates at NBs in PML positive cells but PML I, II, III and IV are static at nuclear bodies in PML negative cells, suggesting that these isoforms require additional protein partners for efficient exchange. PML V turns over at PML Nbs very slowly supporting the idea of a structural function for this isoform. We also demonstrate that SUMOylation of PML at Lysine positions K160 and/or K490 are required for nuclear body formation in vivo.We propose a model in which the isoform specific residence times of PML provide both, structural stability to function as a scaffold and flexibility to attract specific nuclear proteins for efficient biochemical reactions at the surface of nuclear bodies.
MCS code: 92C37
Promyelocytic Leukaemia Protein nuclear bodies (PML-NBs) are dynamic nuclear protein aggregates. To gain insight in PML-NB function, reductionist and high throughput techniques have been employed to identify PML-NB proteins. Here we present a manually curated network of the PML-NB interactome based on extensive literature review including database information. By compiling 'the PML-ome', we highlighted the presence of interactors in the Small Ubiquitin Like Modifier (SUMO) conjugation pathway. Additionally, we show an enrichment of SUMOylatable proteins in the PML-NBs through an in-house prediction algorithm. Therefore, based on the PML network, we hypothesize that PML-NBs may function as a nuclear SUMOylation hotspot.
Nuclear domains 10 (ND10), alternatively termed PML nuclear bodies (PML-NBs) or PML oncogenic domains (PODs), have been discovered approximately 15 years ago as a nuclear substructure that is targeted by a variety of viruses belonging to different viral families. This review will summarize the most important structural and functional characteristics of ND10 and its major protein constituents followed by a discussion of the current view regarding the role of this subnuclear structure for various DNA and RNA viruses with an emphasis on herpesviruses. It is concluded that accumulating evidence argues for an involvement of ND10 in host antiviral defenses either via mediating an intrinsic immune response against specific viruses or via acting as a component of the cellular interferon pathway.