Liu Ni, Wang Yue, Ashton-Rickardt Philip G
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.
FEBS Lett. 2004 Jul 2;569(1-3):49-53. doi: 10.1016/j.febslet.2004.05.061.
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.
半胱氨酸组织蛋白酶从溶酶体释放到细胞质中可触发细胞死亡程序（PCD），该程序不需要半胱天冬酶执行蛋白酶，而是由有毒活性氧（ROS）介导。在此，我们表明，木瓜蛋白酶样组织蛋白酶的一种细胞质抑制剂——丝氨酸蛋白酶抑制剂2A（Spi2A）——是保护细胞免受肿瘤坏死因子-α触发的非半胱天冬酶依赖性PCD所必需的。在没有半胱天冬酶活性的情况下，Spi2A通过在组织蛋白酶B释放到细胞质后抑制它来抑制PCD。Spi2A还直接保护细胞免受ROS介导的PCD，这与它在抑制非半胱天冬酶依赖性PCD途径中的作用一致。我们得出结论，Spi2A对溶酶体执行蛋白酶的抑制是一种生理机制，通过该机制细胞可免受非半胱天冬酶依赖性程序性细胞死亡的影响。
