Dual Proteolytic Pathways Govern Glycolysis and Immune Competence

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

来源：Cell, 2014, 159(7): 1578-1590.

DOI：10.1016/j.cell.2014.12.001

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-gamma and IL-1 beta. 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.

• 出版日期2014-12-18
• 单位NIH