Abstract
The ability of cells to rapidly detect and react to alterations in their chemical environment, such as pH, ionic strength and redox potential, is essential for cell function and survival. We present here evidence that cells can respond to such environmental alterations by rapid induction of matriptase autoactivation. Specifically, we show that matriptase autoactivation can occur spontaneously at physiological pH, and is significantly enhanced by acidic pH, both in a cell-free system and in living cells. The acid-accelerated autoactivation can be attenuated by chloride, a property that may be part of a safety mechanism to prevent unregulated matriptase autoactivation. Additionally, the thio-redox balance of the environment also modulates matriptase autoactivation. Using the cell-free system, we show that matriptase autoactivation is suppressed by cytosolic reductive factors, with this cytosolic suppression being reverted by the addition of oxidizing agents. In living cells, we observed rapid induction of matriptase autoactivation upon exposure to toxic metal ions known to induce oxidative stress, including CoCl2 and CdCl2. The metal-induced matriptase autoactivation is suppressed by N-acetylcysteine, supporting the putative role of altered cellular redox state in metal induced matriptase autoactivation. Furthermore, matriptase knockdown rendered cells more susceptible to CdCl2-induced cell death compared to control cells. This observation implies that the metal-induced matriptase autoactivation confers cells with the ability to survive exposure to toxic metals and/or oxidative stress. Our results suggest that matriptase can act as a cellular sensor of the chemical environment of the cell that allows the cell to respond to and protect itself from changes in the chemical milieu.
Highlights
Both the intracellular and extracellular chemical environments of a cell play important roles in physiological and pathological processes
We show that pH, thio-redox state and chloride ion concentration impact the ability of matriptase to undergo autoactivation, both in a cell free system and in living cells
All three of these factors are considered to be major indicators of the cellular chemical environment that are altered by numerous biological processes
Summary
Both the intracellular and extracellular chemical environments of a cell play important roles in physiological and pathological processes. The secretory pathway maintains a gradient of decreasing pH from near neutrality in the endoplasmic reticulum (ER) (pH 7.2), to mildly acidic in the Golgi (pH 6.7–6.0), to even more acidic within the secretory granules (pH 5.7–5.2) [1,2,3,4] This pH gradient is essential both for proper protein sorting and processing [5], as well as for the regulation of enzyme activity [6]. The activities of proprotein convertases involved in the proteolytic maturation of prohormones are regulated by the pH gradient in the secretory pathway [6] Another example highlighting the importance of pH in pathophysiological processes is the acidic extracellular environment of solid tumors. An example of the importance of extracellular pH and ion concentrations in normal cellular function is the critical pH and calcium gradient required for proper epidermal differentiation and the skin barrier function of the epidermis [9]
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