Serine protease inhibitor 2A inhibits caspase-independent cell death.
The release of cysteine cathepsins from the lysosome into the cytoplasm can trigger programs of cell death (PCD) that do not require caspase executioner proteases but instead are mediated by toxic reactive oxygen species (ROS). Here, we show that a cytoplasmic inhibitor of papain-like cathepsins - Serine protease inhibitor 2A (Spi2A) - is required for the protection of cells from caspase-independent PCD triggered by tumor necrosis factor-alpha. In the absence of caspase activity, Spi2A suppressed PCD by inhibiting cathepsin B after it was released into the cytoplasm. Spi2A also directly protected against ROS-mediated PCD, which is consistent with a role in suppressing caspase-independent pathways of PCD. We conclude that inhibition of lysosomal executioner proteases by Spi2A is a physiological mechanism by which cells are protected from caspase-independent programmed cell death.
Liu
Ni
N
Gwen Knapp Center for Lupus and Immunology Research, Department of Pathology and The Ben May Institute for Cancer Research, The University of Chicago, 924 E. 57th Street, Chicago, IL 60637, USA.
Wang
Yue
Y
Ashton-Rickardt
Philip G
PG
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D015843:Serpins; D014162:Transfection
D009687:Nuclear Proteins; C490400:Serpina3k protein, mouse; D015843:Serpins; D020169:Caspases