PML positively regulates interferon gamma signaling.
PML, also known as TRIM19, belongs to the family encoding a characteristic RBCC/TRIM motif comprising several cysteine-rich zinc-binding domains (RING and B-boxes) and a coiled-coil domain. The RBCC domain and the covalent modification of PML by the small ubiquitin-like modifier (SUMO) are required for PML localization within the nuclear bodies (NBs). Analysis of PML(-/-) mice provided evidence for a physiological role of PML in apoptosis. Cells derived from these mice are defective in the induction of apoptosis by interferon (IFN). PML is expressed as a family of cytoplasmic and nuclear isoforms (PML I-VII) as a result of alternative splicing. Herein, we show that overexpression of all nuclear PML isoforms (I-VI) in human cells increased IFNγ-induced STAT1 phosphorylation, resulting in higher binding of STAT1 to DNA, higher activation of IFN-stimulated genes (ISGs), and an increase in the expression of their products. These effects, observed with IFNγ and not IFNα, required PML localization in the nucleus as they were not observed with the cytoplasmic isoform PMLVIIb or the cytoplasmic variants of PMLIV. They also necessitated PML SUMOylation and its RING finger domain. Conversely, downregulation of PML by RNA interference was accompanied by decrease in IFNγ-induced STAT1 phosphorylation, STAT1 DNA binding, transcription of ISGs and in the expression of their products. In addition, IFNγ-mediated STAT1 DNA-binding activity was decreased in PML(-/-) MEFs compared with wild-type MEFs. Taken together these results demonstrate that PML functions as a positive regulator of IFNγ signaling.
CNRS FRE3238, Institut André Lwoff, 7 rue Guy Môquet, Villejuif Cedex, France.
Jamila
J
El Bougrini
Laurent
L
Dianoux
Mounira K
MK
Chelbi-Alix
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054829:RING Finger Domains; D034622:RNA Interference; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058207:Sumoylation / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine
D050856:Interferon Regulatory Factor-1; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D050794:STAT1 Transcription Factor; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014443:Tyrosine; D007371:Interferon-gamma; D004247:DNA