scholarly journals Overexpression of Promyelocytic Leukemia Protein and Alteration of PML Nuclear Bodies in Early Stage of Hepatocarcinogenesis

2001 ◽  
Vol 16 (4) ◽  
pp. 433 ◽  
Author(s):  
Ghil Suk Yoon ◽  
Eunsil Yu
Keyword(s):  
Early Stage ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Promyelocytic Leukemia Protein ◽  
Pml Nuclear Bodies

scholarly journals Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms

2002 ◽  
Vol 157 (6) ◽  
pp. 975-984 ◽  
Author(s):  
Michael Morgan ◽  
Jacqueline Thorburn ◽  
Pier Paolo Pandolfi ◽  
Andrew Thorburn
Keyword(s):  
Nuclear Export ◽  
Tumor Necrosis Factor Receptor ◽  
Promyelocytic Leukemia ◽  
Dominant Negative ◽  
Nuclear Bodies ◽  
Death Domain ◽  
Apoptosis Pathway ◽  
Promyelocytic Leukemia Protein ◽  
Caspase Inhibitors ◽  
Pml Nuclear Bodies

The adapter protein tumor necrosis factor receptor (TNFR)1–associated death domain (TRADD) plays an essential role in recruiting signaling molecules to the TNFRI receptor complex at the cell membrane. Here we show that TRADD contains a nuclear export and import sequence that allow shuttling between the nucleus and the cytoplasm. In the absence of export, TRADD is found within nuclear structures that are associated with promyelocytic leukemia protein (PML) nuclear bodies. In these structures, the TRADD death domain (TRADD-DD) can activate an apoptosis pathway that is mechanistically distinct from its action at the membrane-bound TNFR1 complex. Apoptosis by nuclear TRADD-DD is promyelocytic leukemia protein dependent, involves p53, and is inhibited by Bcl-xL but not by caspase inhibitors or dominant negative FADD (FADD-DN). Conversely, apoptosis induced by TRADD in the cytoplasm is resistant to Bcl-xL, but sensitive to caspase inhibitors and FADD-DN. These data indicate that nucleocytoplasmic shuttling of TRADD leads to the activation of distinct apoptosis mechanisms that connect the death receptor apparatus to nuclear events.

scholarly journals Promyelocytic Leukemia Protein (PML) Requirement for Interferon-induced Global Cellular SUMOylation

2018 ◽  
Vol 17 (6) ◽  
pp. 1196-1208 ◽  
Author(s):  
Mohamed Ali Maroui ◽  
Ghizlane Maarifi ◽  
Francis P. McManus ◽  
Frédéric Lamoliatte ◽  
Pierre Thibault ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Nuclear Matrix ◽  
Large Scale ◽  
Differential Regulation ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Promyelocytic Leukemia Protein ◽  
Pml Nuclear Bodies ◽  
Key Players ◽  
Sumo E3 Ligase

We report that interferon (IFN) α treatment at short and long periods increases the global cellular SUMOylation and requires the presence of the SUMO E3 ligase promyelocytic leukemia protein (PML), the organizer of PML nuclear bodies (NBs). Several PML isoforms (PMLI-PMLVII) derived from a single PML gene by alternative splicing, share the same N-terminal region but differ in their C-terminal sequences. Introducing each of the human PML isoform in PML-negative cells revealed that enhanced SUMOylation in response to IFN is orchestrated by PMLIII and PMLIV. Large-scale proteomics experiments enabled the identification of 558 SUMO sites on 389 proteins, of which 172 sites showed differential regulation upon IFNα stimulation, including K49 from UBC9, the sole SUMO E2 protein. Furthermore, IFNα induces PML-dependent UBC9 transfer to the nuclear matrix where it colocalizes with PML within the NBs and enhances cellular SUMOylation levels. Our results demonstrate that SUMOylated UBC9 and PML are key players for IFN-increased cellular SUMOylation.

scholarly journals Promyelocytic Leukemia Protein (PML) Controls Listeria monocytogenes Infection

mBio ◽  
2017 ◽  
Vol 8 (1) ◽  
Author(s):  
David Ribet ◽  
Valérie Lallemand-Breitenbach ◽  
Omar Ferhi ◽  
Marie-Anne Nahori ◽  
Hugo Varet ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Listeriolysin O ◽  
Promyelocytic Leukemia Protein ◽  
Cellular Processes ◽  
Pml Nuclear Bodies ◽  
Immunity Genes ◽  
Intracellular Multiplication

ABSTRACT The promyelocytic leukemia protein (PML) is the main organizer of stress-responsive subnuclear structures called PML nuclear bodies. These structures recruit multiple interactors and modulate their abundance or their posttranslational modifications, notably by the SUMO ubiquitin-like modifiers. The involvement of PML in antiviral responses is well established. In contrast, the role of PML in bacterial infection remains poorly characterized. Here, we show that PML restricts infection by the pathogenic bacterium Listeria monocytogenes but not by Salmonella enterica serovar Typhimurium. During infection, PML undergoes oxidation-mediated multimerization, associates with the nuclear matrix, and becomes de-SUMOylated due to the pore-forming activity of the Listeria toxin listeriolysin O (LLO). These events trigger an antibacterial response that is not observed during in vitro infection by an LLO-defective Listeria mutant, but which can be phenocopied by specific induction of PML de-SUMOylation. Using transcriptomic and proteomic microarrays, we also characterized a network of immunity genes and cytokines, which are regulated by PML in response to Listeria infection but independently from the listeriolysin O toxin. Our study thus highlights two mechanistically distinct complementary roles of PML in host responses against bacterial infection. IMPORTANCE The promyelocytic leukemia protein (PML) is a eukaryotic protein that can polymerize in discrete nuclear assemblies known as PML nuclear bodies (NBs) and plays essential roles in many different cellular processes. Key to its function, PML can be posttranslationally modified by SUMO, a ubiquitin-like modifier. Identification of the role of PML in antiviral defenses has been deeply documented. In contrast, the role of PML in antibacterial defenses remains elusive. Here, we identify two mechanistically distinct complementary roles of PML in antibacterial responses against pathogens such as Listeria: (i) we show that PML regulates the expression of immunity genes in response to bacterial infection, and (ii) we unveil the fact that modification of PML SUMOylation by bacterial pore-forming toxins is sensed as a danger signal, leading to a restriction of bacterial intracellular multiplication. Taken together, our data reinforce the concept that intranuclear bodies can dynamically regulate important processes, such as defense against invaders. IMPORTANCE The promyelocytic leukemia protein (PML) is a eukaryotic protein that can polymerize in discrete nuclear assemblies known as PML nuclear bodies (NBs) and plays essential roles in many different cellular processes. Key to its function, PML can be posttranslationally modified by SUMO, a ubiquitin-like modifier. Identification of the role of PML in antiviral defenses has been deeply documented. In contrast, the role of PML in antibacterial defenses remains elusive. Here, we identify two mechanistically distinct complementary roles of PML in antibacterial responses against pathogens such as Listeria: (i) we show that PML regulates the expression of immunity genes in response to bacterial infection, and (ii) we unveil the fact that modification of PML SUMOylation by bacterial pore-forming toxins is sensed as a danger signal, leading to a restriction of bacterial intracellular multiplication. Taken together, our data reinforce the concept that intranuclear bodies can dynamically regulate important processes, such as defense against invaders.

scholarly journals PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence

2015 ◽  
Vol 112 (46) ◽  
pp. 14278-14283 ◽  
Author(s):  
Lisa Ivanschitz ◽  
Yuki Takahashi ◽  
Florence Jollivet ◽  
Olivier Ayrault ◽  
Morgane Le Bras ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Tumor Suppressors ◽  
Splice Variants ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Promyelocytic Leukemia Protein ◽  
Sumo Conjugation ◽  
Multiple Partners ◽  
Pml Nuclear Bodies ◽  
P53 Activation

Promyelocytic leukemia protein (PML) nuclear bodies (NBs) recruit multiple partners, including p53 and many of its regulators. NBs are believed to facilitate several posttranslational modifications and are key regulators of senescence. PML, the organizer of NBs, is expressed as a number of splice variants that all efficiently recruit p53 partners. However, overexpression of only one of them, PML IV, triggers p53-driven senescence. Here, we show that PML IV specifically binds ARF, a key p53 regulator. Similar to ARF, PML IV enhances global SUMO-1 conjugation, particularly that of p53, resulting in p53 stabilization and activation. ARF interacts with and stabilizes the NB-associated UBC9 SUMO-conjugating enzyme, possibly explaining PML IV-enhanced SUMOylation. These results unexpectedly link two key tumor suppressors, highlighting their convergence for global control of SUMO conjugation, p53 activation, and senescence induction.

scholarly journals Promyelocytic leukemia protein (PML) promotes the phenotypic switch of smooth muscle cells in atherosclerotic plaques of human coronary arteries

2021 ◽  
Author(s):  
Weronika Karle ◽  
Samuel Becker ◽  
Philipp Stenzel ◽  
Christoph Knosalla ◽  
Günter Siegel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Coronary Arteries ◽  
Muscle Cells ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Specific Gene ◽  
Promyelocytic Leukemia Protein ◽  
Pml Nuclear Bodies ◽  
Ifn Γ

Promyelocytic leukemia protein (PML) is a constitutive component of PML nuclear bodies (PML-NBs), which function as stress-regulated SUMOylation factories. Since PML can also act as a regulator of the inflammatory and fibroproliferative responses characteristic of atherosclerosis, we investigated whether PML is implicated in this disease. Immunoblotting, ELISA and immunohistochemistry showed a strong up-regulation of PML in segments of human atherosclerotic coronary arteries compared to non-atherosclerotic ones. In particular, PML was concentrated in PML-NBs from alpha-smooth muscle actin-immunoreactive cells in plaque areas. To identify possible functional consequences of PML-accumulation in this cell-type, differentiated human coronary artery smooth muscle cells (dHCASMCs) were transfected with a vector containing the intact PML-gene. These PML-transfected HCASMCs showed higher levels of SUMO-1-dependent SUMOylated proteins, but lower levels of markers for smooth muscle cell differentiation and revealed more proliferation and migration activities than dHCASMCs transfected with the vector lacking a specific gene insert or with the vector containing a mutated PML-gene coding for a PML-form without SUMOylation activity. When dHCASMCs were incubated with different cytokines, higher PML-levels were observed only after IFN-γ stimulation, while the expression of differentiation markers decreased. However, these phenotypic changes were not observed in dHCASMCs treated with small interfering RNA (siRNA) suppressing PML-expression prior to IFN-γ stimulation. Taken together, our results imply that PML is a previously unknown functional factor in the molecular cascades associated with the pathogenesis of atherosclerosis and is positioned in vascular smooth muscle cells between up-stream IFN-γ activation and downstream SUMOylation.

scholarly journals Interaction of the Adenovirus Type 5 E4 Orf3 Protein with Promyelocytic Leukemia Protein Isoform II Is Required for ND10 Disruption

2006 ◽  
Vol 80 (6) ◽  
pp. 3042-3049 ◽  
Author(s):  
Anne Hoppe ◽  
Stephanie J. Beech ◽  
John Dimmock ◽  
Keith N. Leppard
Keyword(s):  
Adenovirus Type ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Promyelocytic Leukemia Protein ◽  
Orf3 Protein ◽  
Pml Nuclear Bodies ◽  
Nuclear Tracks ◽  
Nuclear Structures

ABSTRACT Nuclear domain 10 (ND10s), or promyelocytic leukemia protein (PML) nuclear bodies, are spherical nuclear structures that require PML proteins for their formation. Many viruses target these structures during infection. The E4 Orf3 protein of adenovirus 5 (Ad5) rearranges ND10s, causing PML to colocalize with Orf3 in nuclear tracks or fibers. There are six different PML isoforms (I to VI) present at ND10s, all sharing a common N terminus but with structural differences at their C termini. In this study, PML II was the only one of these six isoforms that was found to interact directly and specifically with Ad5 E4 Orf3 in vitro and in vivo; these results define a new Orf3 activity. Three of a series of 18 mutant Orf3 proteins were unable to interact with PML II; these were also unable to cause ND10 rearrangement. Moreover, in PML-null cells that contained neoformed ND10s comprising a single PML isoform, only ND10s formed of PML II were rearranged by Orf3. These data show that the interaction between Orf3 and PML II is necessary for ND10 rearrangement to occur. Finally, Orf3 was shown to self-associate in vitro. This activity was absent in mutant Orf3 proteins that were unable to form tracks and to bind PML II. Thus, Orf3 oligomerization may mediate the formation of nuclear tracks in vivo and may also be important for PML II binding.

scholarly journals Role of SUMO in RNF4-mediated Promyelocytic Leukemia Protein (PML) Degradation

2009 ◽  
Vol 284 (24) ◽  
pp. 16595-16608 ◽  
Author(s):  
Yann Percherancier ◽  
Delphine Germain-Desprez ◽  
Frédéric Galisson ◽  
Xavier H. Mascle ◽  
Laurent Dianoux ◽  
...  
Keyword(s):  
Covalent Binding ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Covalent Modification ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Promyelocytic Leukemia Protein ◽  
Pml Nuclear Bodies ◽  
Bret Assay

Promyelocytic leukemia protein (PML) is a tumor suppressor acting as the organizer of subnuclear structures called PML nuclear bodies (NBs). Both covalent modification of PML by the small ubiquitin-like modifier (SUMO) and non-covalent binding of SUMO to the PML SUMO binding domain (SBD) are necessary for PML NB formation and maturation. PML sumoylation and proteasome-dependent degradation induced by the E3 ubiquitin ligase, RNF4, are enhanced by the acute promyelocytic leukemia therapeutic agent, arsenic trioxide (As2O3). Here, we established a novel bioluminescence resonance energy transfer (BRET) assay to dissect and monitor PML/SUMO interactions dynamically in living cells upon addition of therapeutic agents. Using this sensitive and quantitative SUMO BRET assay that distinguishes PML sumoylation from SBD-mediated PML/SUMO non-covalent interactions, we probed the respective roles of covalent and non-covalent PML/SUMO interactions in PML degradation and interaction with RNF4. We found that, although dispensable for As2O3-enhanced PML sumoylation and RNF4 interaction, PML SBD core sequence was required for As2O3- and RNF4-induced PML degradation. As confirmed with a phosphomimetic mutant, phosphorylation of a stretch of serine residues, contained within PML SBD was needed for PML interaction with SUMO-modified protein partners and thus for NB maturation. However, mutation of these serine residues did not impair As2O3- and RNF4-induced PML degradation, contrasting with the known role of these phosphoserine residues for casein kinase 2-promoted PML degradation. Altogether, these data suggest a model whereby sumoylation- and SBD-dependent PML oligomerization within NBs is sufficient for RNF4-mediated PML degradation and does not require the phosphorylation-dependent association of PML with other sumoylated partners.

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