InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: PML

Summary

InnateDB Protein

IDBP-377356.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

PML

Protein Name

promyelocytic leukemia

Synonyms

MYL; PP8675; RNF71; TRIM19;

Species

Homo sapiens

Ensembl Protein

ENSP00000394642

InnateDB Gene

IDBG-21462 (PML)

Protein Structure

UniProt Annotation

Function

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 (HCMV) 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.

Subcellular Localization

Nucleus. Nucleus, nucleoplasm. Cytoplasm. Nucleus, PML body. Nucleus, nucleolus. Endoplasmic reticulum membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}; Cytoplasmic side {ECO:0000250}. Early endosome membrane; Peripheral membrane protein; Cytoplasmic side. Note=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.

Disease Associations

Note=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. {ECO:0000269PubMed:1652369, ECO:0000269PubMed:1720570}.

Tissue Specificity

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 277 experimentally validated interaction(s) in this database.
They are also associated with 22 interaction(s) predicted by orthology.

Experimentally validated
Total	277 [view]
Protein-Protein	275 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	22 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0003677	DNA binding
GO:0003713	transcription coactivator activity
GO:0005515	protein binding
GO:0008270	zinc ion binding
GO:0031625	ubiquitin protein ligase binding
GO:0032183	SUMO binding
GO:0042803	protein homodimerization activity
GO:0046982	protein heterodimerization activity
GO:0050897	cobalt ion binding

Biological Process

GO:0001666	response to hypoxia
GO:0001932	regulation of protein phosphorylation
GO:0002230	positive regulation of defense response to virus by host
GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0006461	protein complex assembly
GO:0006605	protein targeting
GO:0006915	apoptotic process
GO:0006977	DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
GO:0007050	cell cycle arrest
GO:0008285	negative regulation of cell proliferation
GO:0008630	intrinsic apoptotic signaling pathway in response to DNA damage
GO:0010522	regulation of calcium ion transport into cytosol
GO:0016032	viral process
GO:0016525	negative regulation of angiogenesis
GO:0019221	cytokine-mediated signaling pathway
GO:0030308	negative regulation of cell growth
GO:0030578	PML body organization
GO:0031065	positive regulation of histone deacetylation
GO:0032211	negative regulation of telomere maintenance via telomerase
GO:0032469	endoplasmic reticulum calcium ion homeostasis
GO:0032922	circadian regulation of gene expression
GO:0032938	negative regulation of translation in response to oxidative stress
GO:0034097	response to cytokine
GO:0042752	regulation of circadian rhythm
GO:0042771	intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
GO:0043153	entrainment of circadian clock by photoperiod
GO:0043161	proteasome-mediated ubiquitin-dependent protein catabolic process
GO:0045087	innate immune response (InnateDB)
GO:0045892	negative regulation of transcription, DNA-templated
GO:0045930	negative regulation of mitotic cell cycle
GO:0050821	protein stabilization
GO:0051457	maintenance of protein location in nucleus
GO:0051607	defense response to virus
GO:0051974	negative regulation of telomerase activity
GO:0060058	positive regulation of apoptotic process involved in mammary gland involution
GO:0060333	interferon-gamma-mediated signaling pathway
GO:0090398	cellular senescence
GO:1902187	negative regulation of viral release from host cell
GO:2000059	negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process
GO:2000779	regulation of double-strand break repair
GO:2001238	positive regulation of extrinsic apoptotic signaling pathway

Cellular Component

GO:0005622	intracellular
GO:0005634	nucleus
GO:0005654	nucleoplasm
GO:0005730	nucleolus
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0016363	nuclear matrix
GO:0016605	PML body
GO:0031901	early endosome membrane
GO:0031965	nuclear membrane
GO:0042406	extrinsic component of endoplasmic reticulum membrane