Jekyll and Hyde; changing places, changing faces

Reviews in Cell Death and Differentiation are not often concerned with proteases other than caspases, particularly not bacterial ones, however the latest findings on a novel pro-apoptotic molecule, a human homologue of E. coli, HtrA, suggest that this might soon change. Bacterial DegP/HtrA is a heat shock inducible periplasmic serine protease that is necessary for bacterial tolerance to thermal, osmotic and oxidative stress. The mammalian homologue HtrA2/Omi has recently been shown to interact with IAPs in an analogous manner to other IAP antagonists, such as Diablo/Smac.^1,2,3,4 In a novel twist however, not only does HtrA2 promote cell death by antagonizing IAPs but it can also accelerate cell death in a caspase independent fashion through its function as a serine protease.

Like Diablo/Smac,^5,6 HtrA2 is: (a) directed to the mitochondria by an N-terminal mitochondrial import sequence; (b) must be N-terminally processed to expose the conserved IAP binding motif;^7,8 (c) is located predominantly in the intermembrane space of the mitochondria; and (d) is released from the mitochondria, into the cytosol following apoptotic stress where it can interact with IAPs via their baculoviral IAP repeats (BIRs).^1,2,3,4 HtrA2 interacts with mammalian XIAP, cIAP-1, cIAP-2 and baculoviral OpIAP, but not survivin, and can interact with both BIR2 and BIR3 of XIAP but not BIR1.^1,2,3,4 HtrA2 binds with higher affinity to BIR2 than BIR3, whereas the reverse is true for Diablo, suggesting that it may function more efficiently to antagonize XIAP inhibition of caspase 3, than of caspase 9.² Nevertheless, the same critical residues within the grooves of BIR2 and 3 shown to be important for Diablo interaction^9,10 are also important for interaction with HtrA2.^1,2,3,4 Furthermore, like Diablo and cytochrome c, release of HtrA2 from the mitochondria can be inhibited by Bcl-2 overexpression.^2,11

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