The IKK complex contributes to the induction of autophagy.
In response to stress, cells start transcriptional and transcription-independent programs that can lead to adaptation or death. Here, we show that multiple inducers of autophagy, including nutrient depletion, trigger the activation of the IKK (IkappaB kinase) complex that is best known for its essential role in the activation of the transcription factor NF-kappaB by stress. Constitutively active IKK subunits stimulated autophagy and transduced multiple signals that operate in starvation-induced autophagy, including the phosphorylation of AMPK and JNK1. Genetic inhibition of the nuclear translocation of NF-kappaB or ablation of the p65/RelA NF-kappaB subunit failed to suppress IKK-induced autophagy, indicating that IKK can promote the autophagic pathway in an NF-kappaB-independent manner. In murine and human cells, knockout and/or knockdown of IKK subunits (but not that of p65) prevented the induction of autophagy in response to multiple stimuli. Moreover, the knockout of IKK-beta suppressed the activation of autophagy by food deprivation or rapamycin injections in vivo, in mice. Altogether, these results indicate that IKK has a cardinal role in the stimulation of autophagy by physiological and pharmacological stimuli.
Criollo
Alfredo
A
INSERM, U848, Villejuif, France.
Senovilla
Laura
L
Authier
Hélène
H
Maiuri
Maria Chiara
MC
Morselli
Eugenia
E
Vitale
Ilio
I
Kepp
Oliver
O
Tasdemir
Ezgi
E
Galluzzi
Lorenzo
L
Shen
Shensi
S
Tailler
Maximilien
M
Delahaye
Nicolas
N
Tesniere
Antoine
A
De Stefano
Daniela
D
Younes
Aména Ben
AB
Harper
Francis
F
Pierron
Gérard
G
Lavandero
Sergio
S
Zitvogel
Laurence
L
Israel
Alain
A
Baud
Véronique
V
Kroemer
Guido
G
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D015398:Signal Transduction / Q000502:physiology
D046912:Multiprotein Complexes; D016328:NF-kappa B; D051550:I-kappa B Kinase