Biologically active proteases are held in check in part by a family of peptidase inhibitors known as serpins. Most serpins are secreted proteins, but some are intracellular proteins implicated in regulating lysosomal proteases. Knockout mice have failed to reveal the biological roles of these inhibitors, though--possibly because mice have some 28 members of the intracellular variety. Therefore, Luke et al. turned to the worm Caenorhabditis elegans, which has about a third as many intracellular serpins. Loss of one of these, 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 as 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 the Rab-like guanosine triphosphatase Glo-1, which is 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, which cause distinct biochemical alterations to initiate cell death, indicate that there may be a central necrotic death mechanism that can be regulated by serpins. If so, serpins could act as an antidote to cells undergoing damage by such stresses, which occur, for example, during heart attacks. Such a prosurvival function of intracellular serpins may help explain why increased expression of some serpin family members is associated with a poor prognosis in various human cancers.
C. J. Luke, S. C. Pak, Y. S. Askew, T. L. Naviglia, D. J. Askew, S. M. Nobar, A. C. Vetica, O. S. Long, S. C. Watkins, D. B. Stolz, R. J. Barstead, G. L. Moulder, D. Brömme, G. A. Silvermann, An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury. Cell, 130, 1108-1119 (2007). [PubMed]