Matriptase autoactivation is tightly regulated by the cellular chemical environments.
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.
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
Jehng-Kang
JK
Wang
Department of Medicine, National Defense Medical Center, Taipei, Taiwan.
I-Jou
IJ
Teng
Department of Medicine, National Defense Medical Center, Taipei, Taiwan.
Ting-Jen
TJ
Lo
Geenebaum Cancer Center, University of Maryland, Baltimore, Maryland, United States of America.
Sean
S
Moore
Department of Medicine, National Defense Medical Center, Taipei, Taiwan.
Yee Hui
YH
Yeo
Department of Biomedical Engineering National Yang Ming University, Taipei, Taiwan.
Yun-Chung
YC
Teng
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
Malvika
M
Kaul
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
Chiann-Chyi
CC
Chen
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, United States of America.
Annie Hong
AH
Zuo
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, United States of America.
Fen-Pai
FP
Chou
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, United States of America.
Xiaoyu
X
Yang
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, United States of America.
I-Chu
IC
Tseng
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, United States of America.
Michael D
MD
Johnson
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, United States of America.
Chen-Yong
CY
Lin
D015153:Blotting, Western; D019256:Cadmium Chloride / Q000633:toxicity; D002460:Cell Line; D002474:Cell-Free System; D060833:Cellular Microenvironment / Q000502:physiology*; D003035:Cobalt / Q000633:toxicity; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D034741:RNA, Small Interfering / Q000235:genetics; D012697:Serine Endopeptidases / Q000378:metabolism*
D034741:RNA, Small Interfering; D003035:Cobalt; D012697:Serine Endopeptidases; C485595:matriptase; C018021:cobaltous chloride; D019256:Cadmium Chloride