PML

Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease characterized by progressive damage or inflammation of the white matter of the brain at multiple locations (multifocal).

PML and PML/RARα chimera

Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. Acts as the scaffold of PML-NBs allowing other proteins to shuttle in and out, a process which is regulated by SUMO-mediated modifications and interactions. Isoform PML-4 has a multifaceted role in the regulation of apoptosis and growth suppression: activates RB1 and inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively, negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53/TP53 by acting at different levels (by promoting its acetylation and phosphorylation and by inhibiting its MDM2-dependent degradation). Isoform PML-4 also: acts as a transcriptional repressor of TBX2 during cellular senescence and the repression is dependent on a functional RBL2/E2F4 repressor complex, regulates double-strand break repair in gamma-irradiation-induced DNA damage responses via its interaction with WRN, acts as a negative regulator of telomerase by interacting with TERT, and regulates PER2 nuclear localization and circadian function. Isoform PML-6 inhibits specifically the activity of the tetrameric form of PKM. The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5) in concert with SATB1 are involved in local chromatin-loop remodeling and gene expression regulation at the MHC-I locus. Isoform PML-2 is required for efficient IFN-gamma induced MHC II gene transcription via regulation of CIITA. Cytoplasmic PML is involved in the regulation of the TGF-beta signaling pathway. PML also regulates transcription activity of ELF4 and can act as an important mediator for TNF-alpha- and IFN-alpha-mediated inhibition of endothelial cell network formation and migration.
Exhibits antiviral activity against both DNA and RNA viruses. The antiviral activity can involve one or several isoform(s) and can be enhanced by the permanent PML-NB-associated protein DAXX or by the recruitment of p53/TP53 within these structures. Isoform PML-4 restricts varicella zoster virus (VZV) via sequestration of virion capsids in PML-NBs thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The sumoylated isoform PML-4 restricts rabies virus by inhibiting viral mRNA and protein synthesis. The cytoplasmic isoform PML-14 can restrict herpes simplex virus-1 (HHV-1) replication by sequestering the viral E3 ubiquitin-protein ligase ICP0 in the cytoplasm. Isoform PML-6 shows restriction activity towards human cytomegalovirus (HHV-5) and influenza A virus strains PR8(H1N1) and ST364(H3N2). Sumoylated isoform PML-4 and isoform PML-12 show antiviral activity against encephalomyocarditis virus (EMCV) by promoting nuclear sequestration of viral polymerase (P3D-POL) within PML NBs. Isoform PML-3 exhibits antiviral activity against poliovirus by inducing apoptosis in infected cells through the recruitment and the activation of p53/TP53 in the PML-NBs. Isoform PML-3 represses human foamy virus (HFV) transcription by complexing the HFV transactivator, bel1/tas, preventing its binding to viral DNA. PML may positively regulate infectious hepatitis C viral (HCV) production and isoform PML-2 may enhance adenovirus transcription. Functions as an E3 SUMO-protein ligase that sumoylates (HHV-5) immediate early protein IE1, thereby participating in the antiviral response (PubMed:20972456, PubMed:28250117).
Isoforms PML-3 and PML-6 display the highest levels of sumoylation activity (PubMed:20972456, PubMed:28250117).

Activation of cysteine-type endopeptidase activity involved in apoptotic processIEA:Ensembl
Apoptotic processIDA:UniProtKB
Branching involved in mammary gland duct morphogenesisIEA:Ensembl
Cell fate commitmentIEA:Ensembl
Cellular response to interleukin-4IEA:Ensembl
Cellular response to leukemia inhibitory factorIEA:Ensembl
Cellular senescenceManual Assertion Based On ExperimentIDA:UniProtKB
Circadian regulation of gene expressionISS:UniProtKB
Common-partner SMAD protein phosphorylationIEA:Ensembl
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrestISS:UniProtKB
Endoplasmic reticulum calcium ion homeostasisISS:UniProtKB
Entrainment of circadian clock by photoperiodISS:UniProtKB
Extrinsic apoptotic signaling pathwayIEA:Ensembl
Fibroblast migrationIEA:Ensembl
Innate immune responseManual Assertion Based On ExperimentIDA:UniProtKB
Intrinsic apoptotic signaling pathway in response to DNA damageManual Assertion Based On ExperimentIDA:UniProtKB
Intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediatorISS:UniProtKB
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stressIEA:Ensembl
Intrinsic apoptotic signaling pathway in response to oxidative stressIEA:Ensembl
Maintenance of protein location in nucleusManual Assertion Based On ExperimentIDA:MGI
Myeloid cell differentiationIEA:Ensembl
Negative regulation of angiogenesisManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of cell growthManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of cell population proliferationManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of interleukin-1 beta productionIEA:Ensembl
Negative regulation of mitotic cell cycleIDA:UniProtKB
Negative regulation of telomerase activityIMP:UniProtKB
Negative regulation of telomere maintenance via telomeraseIMP:UniProtKB
Negative regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of translation in response to oxidative stressIDA:UniProtKB
Negative regulation of ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIMP:UniProtKB
Oncogene-induced cell senescenceIEA:Ensembl
PML body organizationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of apoptotic process involved in mammary gland involutionIDA:UniProtKB
Positive regulation of defense response to virus by hostIMP:UniProtKB
Positive regulation of extrinsic apoptotic signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of fibroblast proliferationIEA:Ensembl
Positive regulation of histone deacetylationIDA:UniProtKB
Positive regulation of peptidyl-lysine acetylationIEA:Ensembl
Positive regulation of protein localization to chromosome, telomeric regionIDA:BHF-UCL
Positive regulation of signal transduction by p53 class mediatorIEA:Ensembl
Positive regulation of telomere maintenanceManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIBA:GO_Central
Proteasome-mediated ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIDA:UniProtKB
Protein import into nucleusIEA:Ensembl
Protein stabilizationIDA:UniProtKB
Protein targetingIDA:UniProtKB
Protein-containing complex assemblyManual Assertion Based On ExperimentIDA:UniProtKB
Protein-containing complex localizationIEA:Ensembl
Regulation of calcium ion transport into cytosolISS:UniProtKB
Regulation of cell adhesionIEA:Ensembl
Regulation of cell cycleIDA:UniProtKB
Regulation of circadian rhythmISS:UniProtKB
Regulation of double-strand break repairManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIMP:UniProtKB
Response to cytokineManual Assertion Based On ExperimentIDA:BHF-UCL
Response to gamma radiationIEA:Ensembl
Response to hypoxiaManual Assertion Based On ExperimentIDA:UniProtKB
Response to UVIEA:Ensembl
Retinoic acid receptor signaling pathwayIEA:Ensembl
Suppression of viral release by hostManual Assertion Based On ExperimentIDA:UniProtKB
Transforming growth factor beta receptor signaling pathwayIEA:Ensembl

Nucleus
Nucleus, nucleoplasm
Cytoplasm
Nucleus, PML body
Nucleus, nucleolus
Endoplasmic reticulum membrane
Early endosome membrane
Isoform PML-1 can shuttle between the nucleus and cytoplasm. Isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6 are nuclear isoforms whereas isoform PML-7 and isoform PML-14 lacking the nuclear localization signal are cytoplasmic isoforms. Detected in the nucleolus after DNA damage. Acetylation at Lys-487 is essential for its nuclear localization. Within the nucleus, most of PML is expressed in the diffuse nuclear fraction of the nucleoplasm and only a small fraction is found in the matrix-associated nuclear bodies (PML-NBs). The transfer of PML from the nucleoplasm to PML-NBs depends on its phosphorylation and sumoylation. The B1 box and the RING finger are also required for the localization in PML-NBs. Also found in specific membrane structures termed mitochondria-associated membranes (MAMs) which connect the endoplasmic reticulum (ER) and the mitochondria. Sequestered in the cytoplasm by interaction with rabies virus phosphoprotein.

A chromosomal aberration involving PML may be a cause of acute promyelocytic leukemia (APL). Translocation t(15;17)(q21;q21) with RARA. The PML breakpoints (type A and type B) lie on either side of an alternatively spliced exon.

Ubiquitinated; mediated by RNF4, RNF111, UHRF1, UBE3A/E6AP, BCR(KLHL20) E3 ubiquitin ligase complex E3 ligase complex, SIAH1 or SIAH2 and leading to subsequent proteasomal degradation (PubMed:18408734, PubMed:21840486, PubMed:22033920).
Ubiquitination by BCR(KLHL20) E3 ubiquitin ligase complex E3 ligase complex requires CDK1/2-mediated phosphorylation at Ser-518 which in turn is recognized by prolyl-isopeptidase PIN1 and PIN1-catalyzed isomerization further potentiates PML interaction with KLHL20 (PubMed:21840486, PubMed:22033920).
'Lys-6'-, 'Lys-11'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination by RNF4 is polysumoylation-dependent (PubMed:18408734).
Ubiquitination by RNF111 is polysumoylation-dependent (By similarity).
Sumoylation regulates PML's: stability in response to extracellular or intracellular stimuli, transcription directly and indirectly, through sequestration of or dissociation of the transcription factors from PML-NBs, ability to regulate apoptosis and its anti-viral activities. It is also essential for: maintaining proper PML nuclear bodies (PML-NBs) structure and normal function, recruitment of components of PML-NBs, the turnover and retention of PML in PML-NBs and the integrity of PML-NBs. Undergoes 'Lys-11'-linked sumoylation. Sumoylation on all three sites (Lys-65, Lys-160 and Lys-490) is required for nuclear body formation. Sumoylation on Lys-160 is a prerequisite for sumoylation on Lys-65. Lys-65 and Lys-160 are sumoylated by PISA1 and PIAS2. PIAS1-mediated sumoylation of PML promotes its interaction with CSNK2A1/CK2 and phosphorylation at Ser-565 which in turn triggers its ubiquitin-mediated degradation. PIAS1-mediated sumoylation of PML-RARA promotes its ubiquitin-mediated degradation. The PML-RARA fusion protein requires the coiled-coil domain for sumoylation. Sumoylation at Lys-490 by RANBP2 is essential for the proper assembly of PML-NBs. SUMO1P1/SUMO5 conjugated PML at Lys-160, Lys-380, Lys-400, Lys-490 and Lys-497, but Lys-380, Lys-400 and Lys-497 are not key acceptor lysines. SUMO1P1/SUMO5 forms polymeric chain on Lys-160 of PML by successive conjugation at 'Lys-18'; facilitating recruitment of PML-NB components, which enlarges PML. SUMO1P1/SUMO5 conjugation of PML increases SUMO2/3 conjugation, which leads to the recruitment of RNF4 and ubiquitin-dependent disintegration of PML-NBs. SUMO1P1/SUMO5 monoconjugated Lys-490 (PubMed:27211601).
DNA damage triggers its sumoylation while some but not all viral infections can abolish sumoylation. Desumoylated by SENP1, SENP2, SENP3, SENP5 and SENP6 (PubMed:27211601, PubMed:12419228, PubMed:21148299).
Arsenic induces PML and PML-RARA polysumoylation and their subsequent RNF4-dependent ubiquitination and proteasomal degradation, and is used as treatment in acute promyelocytic leukemia (APL). The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6) show an increased sumoylation in response to arsenic trioxide. The cytoplasmic isoform PML-7 is not sumoylated.
Phosphorylation is a major regulatory mechanism that controls PML protein abundance and the number and size of PML nuclear bodies (PML-NBs). Phosphorylated in response to DNA damage, probably by ATR. HIPK2-mediated phosphorylation at Ser-8, Ser-36 and Ser-38 leads to increased accumulation of PML protein and its sumoylation and is required for the maximal pro-apoptotic activity of PML after DNA damage. CHEK2-mediated phosphorylation at Ser-117 is important for PML-mediated apoptosis following DNA damage. MAPK1-mediated phosphorylations at Ser-403, Ser-505, Ser-527 and Ser-530 and CDK1/2-mediated phosphorylation at Ser-518 promote PIN1-dependent PML degradation. CK2-mediated phosphorylation at Ser-565 primes PML ubiquitination via an unidentified ubiquitin ligase.
Acetylation at Lys-487 is essential for its nuclear localization. Deacetylated at Lys-487 by SIRT1 and this deacetylation promotes PML control of PER2 nuclear localization.
(Microbial infection) Immediate early protein IE1 of human cytomegalovirus (HHV-5) interferes with the sumoylation of PML (PubMed:15163746, PubMed:10233977, PubMed:27903803).
Immediate early protein IE1 inhibits PML de novo sumoylation (PubMed:27903803).
(Microbial infection) Cleaved at two different sites by enterovirus 71 protease 3C, leading to impaired PML-Nuclear bodies formation.