Lysosomal metal, redox and proton cycles influencing the CysHis cathepsin reaction

Abstract

In the 1930's pioneers discovered that maximal autolysis in tissue homogenates requires metal chelator, sulfhydryl reducing agent and acid pH. However, metals, reducing equivalents and protons (MR&P) have been overlooked as combined catalytic controls. Three categories of lysosomal machinery drive three distinguishable cycles importing and exporting MR&P. Zn²⁺ preemptively inhibits CysHis catalysis under otherwise optimal protonation and reduction. Protein-bound cell Zn²⁺ concentration is 200–2000 times the non-sequestered inhibitory concentration. Following autophagy, lysosomal proteolysis liberates much inhibitory Zn²⁺. The vacuolar proton pump is the driving force for Zn²⁺ export, as well as protonation of the peptidolytic mechanism. Other machinery of lysosomal cycles includes proton-driven Zn²⁺ exporters (e.g. SLC11A1), Zn²⁺ channels (e.g. TRPML-1), lysosomal thiol reductase, etc. The CysHis dyad is a sensor of the vacuolar environment of MR&P, an integrator of these simultaneous variables, and a catalytic responder. Rate-determination can shift between autophagic substrate acquisition (swallowing) and substrate degradation (digesting). Zn²⁺ recycling from degraded proteins to new proteins is a fourth cycle that might pace lysosomal function under some conditions. Heritable insufficient or excess functions of CysHis cathepsins are associated with dysfunctional inflammation and immunity/auto-immunity, including diabetic pathogenesis.