c-Myc activation by Theileria parasites promotes survival of infected B-lymphocytes.
Theileria parasites infect and transform bovine lymphocytes, but host cell immortalization is reversible, as upon parasite death the lymphocytes rapidly die of apoptosis. Infection leads to a marked augmentation in the levels of lymphocyte c-Myc, and the parasite achieves this by inducing increased c-myc transcription and by prolonging the half-life of the transcription factor. Reduction in c-Myc turnover can be ascribed to CK2-mediated phosphorylation of the transcription factor. A parasite-dependent GM-CSF autocrine loop activates a JAK2/STAT3 signalling pathway that contributes to heightened c-myc transcription, and inhibition of the pathway leads to caspase 9 activation and apoptosis that can be directly ascribed to a reduction in c-Myc. An antiapoptotic role for c-Myc was clearly demonstrated by specific inhibition of c-myc expression with antisense oligonucleotides, and this correlates with loss of the antiapoptotic protein Mcl-1, and, consistently, ectopic expression of c-Myc abrogates B-cell death induced upon JAK2 inhibition. Thus, Theileria parasites ensure the survival of their host lymphocytes via specific activation of c-Myc.
Dessauge
Frédéric
F
Laboratoire de Signalisation Immunoparasitaire, CNRS URA CNRS 2581, Département de Parasitologie, Institut Pasteur, Batiment Elie Metchnikoff, 25-28 rue du Dr Roux, 75724 Paris Cedex 15, France.
Hilaly
Sophia
S
Baumgartner
Martin
M
Blumen
Brigitte
B
Werling
Dirk
D
Langsley
Gordon
G
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001402:B-Lymphocytes / Q000502:physiology*; D047390:Casein Kinase II / Q000494:pharmacology; D018929:Cell Culture Techniques; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D016259:Genes, myc; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006207:Half-Life; D006801:Humans; D053614:Janus Kinase 2; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D016794:Theileria / Q000472:pathogenicity*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D047390:Casein Kinase II