Cells degrade proteins via cytosolic proteasomes or vesicular lysosomes, followed by further processing by peptidases to allow recycling of amino acids. In Cell, Lu et al. identify several kindreds associated with genetic deficiency in the expression of tripeptidyl peptidase II (TPPII). Patients present with multiple immunological deficiencies and autoimmunity and encounter recurrent bacterial and viral infections. TPPII functions downstream of proteasomes. Loss of TPPII alters amino acid homeostasis in cells, which triggers a compensatory increase in lysosomal protein-degradation pathways. However, increased lysosomal activity leads to further defects in cellular metabolism by catabolism of the key glycolytic enzyme hexokinase-2, which decreases the glycolytic capacity of the affected cells. As glycolysis is required for many functions of activated cells of the immune system, loss of TPPII activity severely affects the proliferation and effector function of these cells, as observed in the affected patients.

Cell 159, 1578–1590 (2014)