Skip to main content

Advertisement

Log in

Alterations in the Expression of the Anti-Apoptotic Factor HAX-1 upon Seizures-Induced Hippocampal Injury in the Neonatal Rat Brain

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

HS1-associated protein X1 (HAX-1) is a mitochondrial protein which interacts with a diverse group of molecules such as inflammatory cytokines; interleukin-1, hematopoietic lineage specific protein-1 and vimentin. It has been reported that HAX-1 may act as antiapoptotic protein in HeLa- and Jurkat cells after Fas-treatment, irradiation or serum deprivation. This underlines the evidence that HAX-1 might be involved in both receptor- and mitochondria-mediated apoptosis pathways. However, the role of HAX-1 in neuronal death induced by status epilepticus in the immature brain has not been reported. In this study, we performed a status epilepticus in rats and investigated the dynamic changes of HAX-1 expression, HtrA2 distribution and caspase-3 activation in the hippocampus. Western blot and immunohistochemistry analysis revealed that HAX-1 was expressed at very low levels in the hippocampus. Status epilepticus in the immature brain significantly induced increased cytosolic accumulation of HAX-1 in a biphasic manner, induced an upregulation of HtrA2 and enhanced caspase-3 activity in the selectively vulnerable hippocampal CA1-subfield. Taken together, these results suggested that HAX-1 is probably involved in the pathophysiology of cell death induced by epilepsy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Niquet J, Auvin S, Archie M, Seo DW, Allen S, Sankar R, Wasterlain CW (2007) Status epilepticus triggers caspase-3 activation and necrosis in the immature rat brain. Epilepsia 48:1203–1206

    Article  PubMed  Google Scholar 

  2. Holcik M, Gibson H, Korneluk RG (2001) XIAP: apoptotic brake and promising therapeutic. Apoptosis 6:253–261

    Article  PubMed  CAS  Google Scholar 

  3. Rami A, Bechmann I, Stehle J (2008) Exploiting endogenous anti-apoptotic proteins for novel therapeutic strategies in cerebral ischemia. Prog Neurobiol 85:273–296

    Article  PubMed  CAS  Google Scholar 

  4. Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899–1911

    Article  PubMed  CAS  Google Scholar 

  5. Suzuki Y, Demoliere C, Kitamura D, Takeshita H, Deuschle U, Watanabe T (1997) HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases. J Immunol 158:2736–2744

    PubMed  CAS  Google Scholar 

  6. Yamanashi Y, Fukuda T, Nishizumi H, Inazu T, Higashi K, Kitamura D, Ishida T, Yamamura H, Watanabe T, Yamamoto T (1997) Role of tyrosine phosphorylation of HS1 in B cell antigen receptor-mediated apoptosis. J Exp Med 185:1387–1392

    Article  PubMed  CAS  Google Scholar 

  7. Carlsson G, Elinder G, Malmgren H, Trebinska A, Grzybowska E, Dahl N, Nordenskjöld M, Fadeel B (2009) Compound heterozygous HAX1 mutations in a Swedish patient with severe congenital neutropenia and no neurodevelopmental abnormalities. Pediatr Blood Cancer 53:1143–1146

    Article  PubMed  Google Scholar 

  8. Fadeel B, Grzybowska E (2009) HAX-1: a multifunctional protein with emerging roles in human disease. Biochim Biophys Acta 1790:1139–1148

    Article  PubMed  CAS  Google Scholar 

  9. Rezaei N, Chavoshzadeh Z, Alaei OR, Sandrock I, Klein C (2007) Association of HAX1 deficiency with neurological disorder. Neuropediatrics 38:261–263

    Article  PubMed  CAS  Google Scholar 

  10. Chao JR, Parganas E, Boyd K, Hong CY, Opferman JT, Ihle JN (2008) Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 452:98–102

    Article  PubMed  CAS  Google Scholar 

  11. Carlsson G, Melin M, Dahl N, Ramme KG, Nordenskjöld M, Palmblad J, Henter JI, Fadeel B (2007) Kostmann syndrome or infantile genetic agranulocytosis, part two: understanding the underlying genetic defects in severe congenital neutropenia. Acta Paediatr 96:813–819

    Article  PubMed  Google Scholar 

  12. Cilenti L, Soundarapandian MM, Kyriazis GA, Stratico V, Singh S, Gupta S, Bonventre JV, Alnemri ES, Zervos AS (2004) Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death. J Biol Chem 279:50295–50301

    Article  PubMed  CAS  Google Scholar 

  13. Han Y, Chen YS, Liu Z, Bodyak N, Rigor D, Bisping E, Pu WT, Kang PM (2006) Overexpression of HAX-1 protects cardiac myocytes from apoptosis through caspase-9 inhibition. Circ Res 99:415–423

    Article  PubMed  CAS  Google Scholar 

  14. Lee AY, Lee Y, Park YK, Bae KH, Cho S, Lee do H, Park BC, Kang S, Park SG (2008) HS 1-associated protein X-1 is cleaved by caspase-3 during apoptosis. Mol Cells 25:86–90

    PubMed  CAS  Google Scholar 

  15. Rami A, Kim M, Niquet J (2010) Translocation of the serine protease Omi/HtrA2 from mitochondria into the cytosol upon seizure-induced hippocampal injury in the neonatal rat brain. Neurochem Res 35:2199–21207

    Article  PubMed  CAS  Google Scholar 

  16. Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32:281–294

    Article  PubMed  CAS  Google Scholar 

  17. Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R (2001) A serine protease, Omi/HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8:613–621

    Article  PubMed  CAS  Google Scholar 

  18. Vaux DL, Silke J (2003) Mammalian mitochondrial IAP binding proteins. Biochem Biophys Res Commun 304:499–504

    Article  PubMed  CAS  Google Scholar 

  19. Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL (2002) Omi/HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem 277:445–454

    Article  PubMed  CAS  Google Scholar 

  20. Siegelin MD, Kossatz LS, Winckler J, Rami A (2005) Regulation of XIAP and Smac/DIABLO in the rat hippocampus following transient forebrain ischemia. Neurochem Int 46:41–51

    Article  PubMed  CAS  Google Scholar 

  21. Blink E, Maianski NA, Alnemri ES, Zervos AS, Roos D, Kuijpers TW (2003) Intramitochondrial serine protease activity of Omi/HtrA2 is required for caspase-independent cell death of human neutrophils. Cell Death Differ 11:937–949

    Article  Google Scholar 

  22. Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 277:432–438

    Article  PubMed  CAS  Google Scholar 

  23. Vafiadaki E, Sanoudou D, Arvanitis DA, Catino DH, Kranias EG (2007) Kontrogianni-Konstantopoulos A. Phospholamban interacts with HAX-1, a mitochondrial protein with anti-apoptotic function. J Mol Biol 367:65–79

    Article  PubMed  CAS  Google Scholar 

  24. Sharp TV, Wang HW, Koumi A, Hollyman D, Endo Y, Ye H, Du MQ, Boshoff C (2002) K15 protein of Kaposi’s sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. J Virol 76:802–816

    Article  PubMed  CAS  Google Scholar 

  25. Mirmohammadsadegh A, Tartler U, Michel G, Baer A, Walz M, Wolf R, Ruzicka T, Hengge UR (2003) HAX-1, identified by differential display reverse transcription polymerase chain reaction, is overexpressed in lesional psoriasis. J Invest Dermatol 120:1045–1051

    Article  PubMed  CAS  Google Scholar 

  26. Kang YJ, Jang M, Park YK, Kang S, Bae KH, Cho S, Lee CK, Park BC, Chi SW, Park SG (2010) Molecular interaction between HAX-1 and XIAP inhibits apoptosis. Biochem Biophys Res Commun 393:794–799

    Article  PubMed  CAS  Google Scholar 

  27. Althaus J, Siegelin MD, Dehghani F, Cilenti L, Zervos AS, Rami A (2007) The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion. Neurochem Int 50:172–180

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Prof. Jörg Stehle for continuous support to our work. This study was funded in part by research grant from the Adolf-Messer-Stiftung (Grant to Dr. A. Rami).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A. Rami.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rami, A., Kim, M., Niquet, J. et al. Alterations in the Expression of the Anti-Apoptotic Factor HAX-1 upon Seizures-Induced Hippocampal Injury in the Neonatal Rat Brain. Neurochem Res 37, 116–125 (2012). https://doi.org/10.1007/s11064-011-0589-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0589-9

Keywords

Navigation