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Serpins Save Cells

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Science  12 Oct 2007:
Vol. 318, Issue 5848, pp. 173
DOI: 10.1126/science.318.5848.173b

Biologically active proteases are held in check in part by a family of peptidase inhibitors known as serpins. Most serpins are secreted, but some are intracellular proteins implicated in regulating lysosomal proteases. Luke et al. found that in the worm Caenorhabditis elegans, loss of the intracellular serpin SRP-6 caused animals to become highly sensitive to hypo-osmotic stress and to die as a result of necrotic cell death. This effect appeared to require inhibition of cysteine peptidases because survival of the knockout worms was improved in mutant animals engineered to express wild-type SRP-6 but not in animals that expressed a mutant serpin that lacked inhibitory activity. Calcium mobilization appeared to be required for cell death because SRP-6 knockout animals lacking the ryanodine receptor, the inositol-1,4,5-trisphosphate receptor, or the Ca2+-binding protein calreticulin showed suppression of cell death. Lysosome-like gut granules also appeared to be required, because death was suppressed in animals lacking a guanosine triphosphatase required for formation of these acidic granules. Animals lacking SRP-6 were also more susceptible than wild-type animals to heat shock, hypoxia, or hyperoxia. The authors argue that the common effects of serpins on these stimuli may indicate that there is a central necrotic death mechanism that can be regulated by serpins. If so, serpins could act as an antidote to cells undergoing, for example, hypoxic stress during heart attacks. Such a prosurvival function of intracellular serpins might also explain why increased expression of some serpin family members portends a poor prognosis in various human cancers. — LBR

Cell 130, 1108 (2007).

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