Negative regulation of AMPK signaling by high glucose via E3 ubiquitin ligase MG53.
Mol Cell
; 81(3): 629-637.e5, 2021 02 04.
Article
en En
| MEDLINE
| ID: mdl-33400924
ABSTRACT
As a master regulator of metabolism, AMP-activated protein kinase (AMPK) is activated upon energy and glucose shortage but suppressed upon overnutrition. Exaggerated negative regulation of AMPK signaling by nutrient overload plays a crucial role in metabolic diseases. However, the mechanism underlying the negative regulation is poorly understood. Here, we demonstrate that high glucose represses AMPK signaling via MG53 (also called TRIM72) E3-ubiquitin-ligase-mediated AMPKα degradation and deactivation. Specifically, high-glucose-stimulated reactive oxygen species (ROS) signals AKT to phosphorylate AMPKα at S485/491, which facilitates the recruitment of MG53 and the subsequent ubiquitination and degradation of AMPKα. In addition, high glucose deactivates AMPK by ROS-dependent suppression of phosphorylation of AMPKα at T172. These findings not only delineate the mechanism underlying the impairment of AMPK signaling in overnutrition-related diseases but also highlight the significance of keeping the yin-yang balance of AMPK signaling in the maintenance of metabolic homeostasis.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Músculo Esquelético
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Diabetes Mellitus
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Proteínas Quinasas Activadas por AMP
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Glucosa
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Proteínas de la Membrana
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Obesidad
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Año:
2021
Tipo del documento:
Article