A model of partnership co-opted by the homeodomain protein TGIF and the Itch/AIP4 ubiquitin ligase for effective execution of TNF-alpha cytotoxicity.
The homeodomain protein TGIF functions as a negative regulator of multiple classes of transcription factors. Here we report on the characterization of TGIF as an essential component of the tumor necrosis factor alpha (TNF-alpha) cytotoxic program. This proapoptotic role of TGIF does not appear to rely on transcriptional modulation but instead is executed in conjunction with Itch/AIP4, an E3 ubiquitin ligase operating in TNF-alpha-induced apoptosis through its ability to target the caspase antagonist cFlip(L) for degradation. Notably, we found that activation of TNF-alpha signaling induced the association of TGIF with Itch/AIP4, resulting in increased accessibility of cFlip(L) for association and ubiquitination by Itch/AIP4. Moreover, we show that Itch/AIP4 can also stabilize the TGIF protein in response to TNF-alpha by triggering its monoubiquitination at lysine 259, thereby revealing the existence of a functional network that can evolve into a positive feedback loop for ensuring effective execution of the TNF-alpha apoptotic signaling.
Demange
Christine
C
INSERM U, Paris, France.
Ferrand
Nathalie
N
Prunier
Céline
C
Bourgeade
Marie-Francoise
MF
Atfi
Azeddine
A
D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C097504:TGIF1 protein, human; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; D008239:Lysine