Abstract
Interferons (IFNs) are a family of secreted proteins with antiviral, antiproliferative and immunomodulatory activities. The different biological actions of IFN are believed to be mediated by the products of specifically induced cellular genes in the target cells. The promyelocytic leukaemia (PML) protein localizes both in the nucleoplasm and in matrix-associated multi-protein complexes known as nuclear bodies (NBs). PML is essential for the proper formation and the integrity of the NBs. Modification of PML by the Small Ubiquitin MOdifier (SUMO) was shown to be required for its localization in NBs. The number and the intensity of PML NBs increase in response to interferon (IFN). Inactivation of the IFN-induced PML gene by its fusion to retinoic acid receptor alpha alters the normal localization of PML from the punctuate nuclear patterns of NBs to micro-dispersed tiny dots and results in uncontrolled growth in Acute Promyelocytic Leukaemia. The NBs-associated proteins, PML, Sp100, Sp140, Sp110, ISG20 and PA28 are induced by IFN suggesting that nuclear bodies could play a role in IFN response. Although the function of PML NBs is still unclear, some results indicate that they may represent preferential targets for viral infections and that PML could play a role in the mechanism of the antiviral action of IFNs. Viruses, which require the cellular machinery for their replication, have evolved different ways to counteract the action of IFN by inhibiting IFN signalling, by blocking the activities of specific antiviral mediators or by altering PML expression and/or localization on nuclear bodies.
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Abbreviations
- PML:
-
pro-myelocytic leukaemia
- APL:
-
acute promyelocytic leukaemia
- SUMO:
-
Small Ubiquitin MOdifier
- PKR:
-
protein kinase RNA-dependent
- IRF:
-
interferon regulatory factor
- IFN:
-
interferon
- ISGs:
-
IFN-stimulated genes
- STATs:
-
signal transducers and activators of transcription
- NBs:
-
nuclear bodies
- ISRE:
-
IFN-stimulated response element
- GAS:
-
IFNγ- activated site
- ISGF3:
-
IFN-stimulated gene factor 3
- IFNAR1:
-
IFN-α receptor1
- IFNAR2:
-
IFN-α receptor2
- IFNGR1:
-
IFN-γ receptor1
- IFNGR2:
-
IFN-γ receptor2
- EMCV:
-
encephalomyocarditis
- VSV:
-
vesicular stomatitis virus
- HSV:
-
herpes simplex virus
- LCMV:
-
lymphocytic choriomeningitis virus
- HTLV-1:
-
human T cell leukaemia virus type1
- HDV:
-
hepatitis delta virus
- Tas:
-
transactivator of spumaviruses
- HFV:
-
human foamy virus
- HCV:
-
hepatitis C virus
- HPV:
-
human papilloma virus
- HCMV:
-
human cytomegalovirus
- HCV:
-
hepatitis C virus
- LTR:
-
long terminal repeats
- IP:
-
internal promoter
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Acknowledgements
We thank Roger Everett and all our colleagues from UPR 9045 of Centre National pour la Recherche Scientifique for comments on the manuscript. This work was supported by grants from CNRS and Association pour la Recherche sur le Cancer.
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Regad, T., Chelbi-Alix, M. Role and fate of PML nuclear bodies in response to interferon and viral infections. Oncogene 20, 7274–7286 (2001). https://doi.org/10.1038/sj.onc.1204854
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