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Abstract
Autophagy is involved in both the cell protective and the cell death process but its mechanism is largely unknown. The present work unravels a novel intracellular mechanism by which the serpin α1-antitrypsin (AAT) acts as a novel negative regulator of autophagic cell death. For the first time, the role of intracellularly synthesized AAT, other than in liver cells, is demonstrated. Autophagic cell death was induced by N-α-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and tamoxifen. By utilizing a fluorescently tagged TPCK analog, AAT was "fished out" (pulled out) as a TPCK intracellular protein target. The interaction was further verified by competition binding experiments. Both inducers caused downregulation of AAT expression associated with activation of trypsin-like proteases. Furthermore, silencing AAT by siRNA induced autophagic cell death. Moreover, AAT administration to cultured cells prevented autophagic cell death. This new mechanism could have implications in the treatment of diseases by the regulation of AAT levels in which autophagy has a detrimental function. Furthermore, the results imply that the high synthesis of endogenous AAT by cancer cells could provide a novel resistance mechanism of cancer against autophagic cell death.
Highlights
Autophagy is involved in both cell protective and destructive processes [1,2] in various diseases, such as cancer, neurodegenerative diseases, pathogen invasion and other muscular and liver disorders [3,4,5]
The autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin A1 both suppressed MDC uptake in MCF-7 cells treated with tosyl-L-phenylalanine chloromethyl ketone (TPCK)
We have shown that as α1-antitrypsin (AAT) is a new intracellular regulator of autophagic cell death
Summary
Autophagy is involved in both cell protective and destructive processes [1,2] in various diseases, such as cancer, neurodegenerative diseases, pathogen invasion and other muscular and liver disorders [3,4,5]. The present study reports the novel finding that, in addition to the wellrecognized extracellular AAT activity, this serine protease inhibitor modulates autophagy from within the cell. These results provide a new cellular mechanism regulating autophagic cell death by binding and downregulating the levels of the intracellular synthesized serpin, whose cellular role was hitherto unknown. These findings and our observation that extracellular AAT functions as a negative regulator of autophagy may afford new therapeutic strategies for intervention against diseases in which prevention of autophagy is warranted. Since AAT is already clinically used and is well tolerated even at high concentrations, its way to additional clinical applications will be relatively short
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