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Merck

Dual proteolytic pathways govern glycolysis and immune competence.

Cell (2014-12-20)
Wei Lu, Yu Zhang, David O McDonald, Huie Jing, Bernadette Carroll, Nic Robertson, Qian Zhang, Helen Griffin, Sharon Sanderson, Jeremy H Lakey, Neil V Morgan, Louise N Reynard, Lixin Zheng, Heardley M Murdock, Stuart E Turvey, Scott J Hackett, Tim Prestidge, Julie M Hall, Andrew J Cant, Helen F Matthews, Mauro F Santibanez Koref, Anna Katharina Simon, Viktor I Korolchuk, Michael J Lenardo, Sophie Hambleton, Helen C Su
要旨

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-1β. 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.