Autolysosomal ß-catenin degradation regulates Wnt-autophagy-p62 crosstalk.
EMBO J
; 32(13): 1903-16, 2013 Jul 03.
Article
en En
| MEDLINE
| ID: mdl-23736261
ABSTRACT
The Wnt/ß-catenin signalling and autophagy pathways each play important roles during development, adult tissue homeostasis and tumorigenesis. Here we identify the Wnt/ß-catenin signalling pathway as a negative regulator of both basal and stress-induced autophagy. Manipulation of ß-catenin expression levels in vitro and in vivo revealed that ß-catenin suppresses autophagosome formation and directly represses p62/SQSTM1 (encoding the autophagy adaptor p62) via TCF4. Furthermore, we show that during nutrient deprivation ß-catenin is selectively degraded via the formation of a ß-catenin-LC3 complex, attenuating ß-catenin/TCF-driven transcription and proliferation to favour adaptation during metabolic stress. Formation of the ß-catenin-LC3 complex is mediated by a W/YXXI/L motif and LC3-interacting region (LIR) in ß-catenin, which is required for interaction with LC3 and non-proteasomal degradation of ß-catenin. Thus, Wnt/ß-catenin represses autophagy and p62 expression, while ß-catenin is itself targeted for autophagic clearance in autolysosomes upon autophagy induction. These findings reveal a regulatory feedback mechanism that place ß-catenin at a key cellular integration point coordinating proliferation with autophagy, with implications for targeting these pathways for cancer therapy.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autofagia
/
Factores de Transcripción
/
Neoplasias del Colon
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Proteínas Adaptadoras Transductoras de Señales
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Proteínas Wnt
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Beta Catenina
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice
/
Lisosomas
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
EMBO J
Año:
2013
Tipo del documento:
Article
País de afiliación:
Reino Unido