Abstract
Accumulating reports demonstrate that apoptosis does not explain all the forms of programmed cell death (PCD), particularly in individual development and neurodegenerative disease. Recently, a novel type of PCD, designated 'paraptosis', was described. Here, we show that overexpression of TAJ/TROY, a member of the tumor necrosis factor receptor superfamily, induces non-apoptotic cell death with paraptosis-like morphology in 293T cells. Transmission electron microscopy studies reveal extensive cytoplasmic vacuolation and mitochondrial swelling in some dying cells and no condensation or fragmentation of the nuclei. Characteristically, cell death triggered by TAJ/TROY was accompanied by phosphatidylserine externalization, loss of the mitochondrial transmembrane potential and independent of caspase activation. In addition, TAJ/TROY suppressed clonogenic growth of HEK293 and HeLa cells. Interestingly, overexpression of Programmed cell death 5 (PDCD5), an apoptosis-promoting protein, enhanced TAJ/TROY-induced paraptotic cell death. Moreover, cellular endogenous PDCD5 protein was significantly upregulated in response to TAJ/TROY overexpression. These results provide novel evidence that TAJ/TROY activates a death pathway distinct from apoptosis and that PDCD5 is an important regulator in both apoptotic and non-apoptotic PCD.
Highlights
Apoptosis is a common, conserved, endogenous cell suicide program required for proper embryonic development and maintenance of homeostasis in adult tissues (Vaux and Korsmeyer, 1999; Jacobson et al, 1997)
Ultrastructural analyses revealed that TAJ/TROY-induced cell death was distinct from apoptosis
We propose that TAJ/TROY-transfected cells died through a paraptotic mechanism
Summary
Apoptosis is a common, conserved, endogenous cell suicide program required for proper embryonic development and maintenance of homeostasis in adult tissues (Vaux and Korsmeyer, 1999; Jacobson et al, 1997). Apoptosis is characterized by a biochemical cascade and morphological changes, including activation of caspases, translocation of phosphatidylserine from the inner to the outer layer of the plasma membrane, blebbing of cytoplasmic membranes, chromatin condensation and fragmentation into apoptotic bodies (Kerr et al, 1972; Thornberry and Lazebnik, 1998; Hengartner, 2000). Ceramide induced non-apoptotic PCD with necroticlike morphology in human glioma cells in the presence of pan-caspase inhibitors or during overexpression of Bcl-xL (Mochizuki et al, 2002). These examples support the theory that cells have other intrinsic programs for death that are distinct from apoptosis. Despite the elucidation of morphological characteristics, the precise biochemical mechanism for non-apoptotic PCD and the basic components of the death machinery are currently unknown
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