Tumor suppressor CYLD regulates JNK-induced cell death in Drosophila.
CYLD encodes a tumor suppressor that is mutated in familial cylindromatosis. Despite biochemical and cell culture studies, the physiological functions of CYLD in animal development and tumorigenesis remain poorly understood. To address these questions, we generated Drosophila CYLD (dCYLD) mutant and transgenic flies expressing wild-type and mutant dCYLD proteins. Here we show that dCYLD is essential for JNK-dependent oxidative stress resistance and normal lifespan. Furthermore, dCYLD regulates TNF-induced JNK activation and cell death through dTRAF2, which acts downstream of the TNF receptor Wengen and upstream of the JNKK kinase dTAK1. We show that dCYLD encodes a deubiquitinating enzyme that deubiquitinates dTRAF2 and prevents dTRAF2 from ubiquitin-mediated proteolytic degradation. These data provide a molecular mechanism for the tumor suppressor function of this evolutionary conserved molecule by indicating that dCYLD plays a critical role in modulating TNF-JNK-mediated cell death.
Xue
Lei
L
Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT 06536, USA.
Igaki
Tatsushi
T
Kuranaga
Erina
E
Kanda
Hiroshi
H
Miura
Masayuki
M
Xu
Tian
T
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D000074749:Deubiquitinating Enzyme CYLD; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017344:Genes, Insect; D016147:Genes, Tumor Suppressor; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008136:Longevity; D009154:Mutation; D018384:Oxidative Stress; D010957:Plasmids; D011233:Precipitin Tests; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D029721:Drosophila Proteins; D047992:TNF Receptor-Associated Factor 2; D025521:Tumor Suppressor Proteins; D048031:JNK Mitogen-Activated Protein Kinases; C523258:CYLD protein, Drosophila; D000074749:Deubiquitinating Enzyme CYLD