Omi/HtrA2 and XIAP are components of platelet apoptosis signalling

Summary

Although platelets possess the hallmarks of apoptosis such as activation of caspases, cytochrome c release and depolarisation of the mitochondrial transmembrane potential (ΔΨm), their entire apoptotic-signalling pathway is not totally understood. Therefore we studied the expression of various apoptotic proteins and found that platelets contain the pro-apoptotic proteins Omi/HtrA2 and Smac/Diablo, as well as their target the X-linked inhibitor of apoptosis XIAP. Omi/HtrA2 and Smac/Diablo were released from mitochondria into the platelet cytosol together with cytochrome c after induction of apoptosis by the Ca²⁺ ionophore A23187 or the BH3 mimetic ABT-737, and to a lesser extent, after platelet stimulation with collagen and thrombin. Inhibition of Omi/HtrA2 led to decreased levels of activated caspase-3/7 and caspase-9, but did not abolish loss of ΔΨm or prevent release of Omi/HtrA2 from mitochondria. These results indicate that platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease Omi/HtrA2 and its target protein XIAP.

Keywords

Apoptosis - caspase-3 - platelets - Omi/HtrA2 - XIAP

• References

• 1 Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407: 770-776.
• 2 Landes T, Martinou JC. Mitochondrial outer membrane permeabilisation during apoptosis: the role of mitochondrial fission. Biochim Biophys Acta 2011; 1813: 540-545.
• 3 Rasola A, Bernardi P. Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. Cell Calcium 2011; 50: 222-233.
• 4 Chai J, Shiozaki E, Srinivasula SM. et al. Structural basis of caspase-7 inhibition by XIAP. Cell 2001; 104: 769-780.
• 5 Martins LM, Iaccarino I, Tenev T. et al. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem 2002; 277: 439-444.
• 6 van Loo G, van Gurp M, Depuydt B. et al. The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ 2002; 9: 20-26.
• 7 Hegde R, Srinivasula SM, Zhang Z. et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 2002; 277: 432-438.
• 8 Srinivasula SM, Datta P, Fan XJ. et al. Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway. J Biol Chem 2000; 275: 36152-36157.
• 9 Kuninaka S, Nomura M, Hirota T. et al. The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death. Oncogene 2005; 24: 5287-5298.
• 10 Yang QH, Church-Hajduk R, Ren J. et al. Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev 2003; 17: 1487-1496.
• 11 Cilenti L, Lee Y, Hess S. et al. Characterisation of a novel and specific inhibitor for the pro-apoptotic protease Omi/HtrA2. J Biol Chem 2003; 278: 11489-11494.
• 12 Cilenti L, Kyriazis GA, Soundarapandian MM. et al. Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells. Am J Physiol Renal Physiol 2005; 288: F371-379.
• 13 Blink E, Maianski NA, Alnemri ES. et al. Intramitochondrial serine protease activity of Omi/HtrA2 is required for caspase-independent cell death of human neutrophils. Cell Death Differ 2004; 11: 937-939.
• 14 Srinivasula SM, Hegde R, Saleh A. et al. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 2001; 410: 112-116.
• 15 Wu G, Chai J, Suber TL. et al. Structural basis of IAP recognition by Smac/DIABLO. Nature 2000; 408: 1008-1012.
• 16 Leytin V. Apoptosis in the anucleate platelet. Blood Rev 2012; 26: 51-63.
• 17 Lopez JJ, Salido GM, Pariente JA. et al. Thrombin induces activation and translocation of Bid, Bax and Bak to the mitochondria in human platelets. J Thromb Haemost 2008; 6: 1780-1788.
• 18 Mason KD, Carpinelli MR, Fletcher JI. et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128: 1173-1186.
• 19 Schoenwaelder SM, Yuan Y, Josefsson EC. et al. Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood 2009; 114: 663-666.
• 20 Lopez JJ, Salido GM, Gomez-Arteta E. et al. Thrombin induces apoptotic events through the generation of reactive oxygen species in human platelets. J Thromb Haemost 2007; 5: 1283-1291.
• 21 Vogler M, Hamali HA, Sun XM. et al. BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation. Blood 2011; 117: 7145-7154.
• 22 Wolf BB, Goldstein JC, Stennicke HR. et al. Calpain functions in a caspase-independent manner to promote apoptosis-like events during platelet activation. Blood 1999; 94: 1683-1692.
• 23 Mutlu A, Gyulkhandanyan AV, Freedman J. et al. Activation of caspases-9, -3 and -8 in human platelets triggered by BH3-only mimetic ABT-737 and calcium ionophore A23187: caspase-8 is activated via bypass of the death receptors. Br J Haematol. 2012 Epub ahead of print.
• 24 Shcherbina A, Remold-O’Donnell E. Role of caspase in a subset of human platelet activation responses. Blood 1999; 93: 4222-4231.
• 25 Winkler J, Kroiss S, Rand ML. et al. Platelet apoptosis in paediatric immune thrombocytopenia is ameliorated by intravenous immunoglobulin. Br J Haematol 2012; 156: 508-515.
• 26 Song S, Crow AR, Freedman J. et al. Monoclonal IgG can ameliorate immune thrombocytopenia in a murine model of ITP: an alternative to IVIG. Blood 2003; 101: 3708-3713.
• 27 Cookson P, Sutherland J, Turner C. et al. Platelet apoptosis and activation in platelet concentrates stored for up to 12 days in plasma or additive solution. Transfus Med 2010; 20: 392-402.
• 28 Leung R, Gwozdz AM, Wang H. et al. Persistence of procoagulant surface expression on activated human platelets: involvement of apoptosis and aminophospholipid translocase activity. J Thromb Haemost 2007; 5: 560-570.
• 29 Schmugge M, Rand ML, Bang KW. et al. The relationship of von Willebrand factor binding to activated platelets from healthy neonates and adults. Pediatr Res 2003; 54: 474-479.
• 30 Plenchette S, Moutet M, Benguella M. et al. Early increase in DcR2 expression and late activation of caspases in the platelet storage lesion. Leukemia 2001; 15: 1572-1581.
• 31 White MJ, Schoenwaelder SM, Josefsson EC. et al. Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function. Blood 2012; 119: 4283-4290.
• 32 Schoenwaelder SM, Jarman KE, Gardiner EE. et al. Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. Blood 2011; 118: 1663-1674.
• 33 Leytin V, Mykhaylov S, Starkey AF. et al. Intravenous immunoglobulin inhibits anti-glycoprotein IIb-induced platelet apoptosis in a murine model of immune thrombocytopenia. Br J Haematol 2006; 133: 78-82.
• 34 Leytin V, Allen DJ, Mykhaylov S. et al. Thrombin-triggered platelet apoptosis. J Thromb Haemost 2006; 4: 2656-2663.
• 35 Vande Walle L, Van Damme P, Lamkanfi M. et al. Proteome-wide Identification of HtrA2/Omi Substrates. J Proteome Res 2007; 6: 1006-1015.