Dual proteolytic pathways govern glycolysis and immune competence.
Cell
; 159(7): 1578-90, 2014 Dec 18.
Article
en En
| MEDLINE
| ID: mdl-25525876
ABSTRACT
Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines, including IFN-γ and IL-1ß. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Serina Endopeptidasas
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Dipeptidil-Peptidasas y Tripeptidil-Peptidasas
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Inmunidad Adaptativa
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Proteolisis
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Glucólisis
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Aminopeptidasas
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Inmunidad Innata
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Síndromes de Inmunodeficiencia
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Cell
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos