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Dual proteolytic pathways govern glycolysis and immune competence.

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-? and IL-1?. 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.

SUBMITTER: Lu W

PROVIDER: S-EPMC4297473 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Dual proteolytic pathways govern glycolysis and immune competence.

Lu Wei W Zhang Yu Y McDonald David O DO Jing Huie H Carroll Bernadette B Robertson Nic N Zhang Qian Q Griffin Helen H Sanderson Sharon S Lakey Jeremy H JH Morgan Neil V NV Reynard Louise N LN Zheng Lixin L Murdock Heardley M HM Turvey Stuart E SE Hackett Scott J SJ Prestidge Tim T Hall Julie M JM Cant Andrew J AJ Matthews Helen F HF Koref Mauro F Santibanez MF Simon Anna Katharina AK Korolchuk Viktor I VI Lenardo Michael J MJ Hambleton Sophie S Su Helen C HC

Cell 20141201 7

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 cell ...[more]

PMID: 25525876

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Dual proteolytic pathways govern glycolysis and immune competence.

Publications

Dual proteolytic pathways govern glycolysis and immune competence.

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