Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos c-Jun activator protein-1 complex that causes apoptosis in macrophages.
Asim, Mohammad, et al.
J. Biol. Chem., 285: 20343-57 (2010)
2010
显示摘要
Macrophages are essential components of innate immunity, and apoptosis of these cells impairs mucosal defense to microbes. Helicobacter pylori is a gastric pathogen that infects half of the world population and causes peptic ulcer disease and gastric cancer. The host inflammatory response fails to eradicate the organism. We have reported that H. pylori induces apoptosis of macrophages by generation of polyamines from ornithine decarboxylase (ODC), which is dependent on c-Myc as a transcriptional enhancer. We have now demonstrated that expression of c-Myc requires phosphorylation and nuclear translocation of ERK, which results in phosphorylation of c-Fos and formation of a specific activator protein (AP)-1 complex. Electromobility shift assay and immunoprecipitation revealed a previously unrecognized complex of phospho-c-Fos (pc-Fos) and c-Jun in the nucleus. Fluorescence resonance energy transfer demonstrated the interaction of pc-Fos and c-Jun. The capacity of this AP-1 complex to bind to putative AP-1 sequences was demonstrated by oligonucleotide pulldown and fluorescence polarization. Binding of the pc-Fos.c-Jun complex to the c-Myc promoter was demonstrated by chromatin immunoprecipitation. A dominant-negative c-Fos inhibited H. pylori-induced expression of c-Myc and ODC and apoptosis. H. pylori infection of mice induced a rapid infiltration of macrophages into the stomach. Concomitant apoptosis depleted these cells, and this was associated with formation of a pc-Fos.c-Jun complex. Treatment of mice with an inhibitor of ERK phosphorylation attenuated phosphorylation of c-Fos, expression of ODC, and apoptosis in gastric macrophages. A unique AP-1 complex in gastric macrophages contributes to the immune escape of H. pylori. | 20410304
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Clastosome: a subtype of nuclear body enriched in 19S and 20S proteasomes, ubiquitin, and protein substrates of proteasome.
Lafarga, Miguel, et al.
Mol. Biol. Cell, 13: 2771-82 (2002)
2002
显示摘要
Nuclear bodies represent a heterogeneous class of nuclear structures. Herein, we describe that a subset of nuclear bodies is highly enriched in components of the ubiquitin-proteasome pathway of proteolysis. We coined the term clastosome (from the Greek klastos, broken and soma, body) to refer to this type of nuclear body. Clastosomes contain a high concentration of 1) ubiquitin conjugates, 2) the proteolytically active 20S core and the 19S regulatory complexes of the 26S proteasome, and 3) protein substrates of the proteasome. Although detected in a variety of cell types, clastosomes are scarce under normal conditions; however, they become more abundant when proteasomal activity is stimulated. In contrast, clastosomes disappear when cells are treated with proteasome inhibitors. Protein substrates of the proteasome that are found concentrated in clastosomes include the short-lived transcription factors c-Fos and c-Jun, adenovirus E1A proteins, and the PML protein. We propose that clastosomes are sites where proteolysis of a variety of protein substrates is taking place. | 12181345
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