Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice

L Miguel Martins, Alastair Morrison, Kristina Klupsch, Valentina Fedele, Nicoleta Moisoi, Peter Teismann, Alejandro Abuin, Evelyn Grau, Martin Geppert, George P Livi, Caretha L Creasy, Alison Martin, Iain Hargreaves, Simon J Heales, Hitoshi Okada, Sebastian Brandner, Jörg B Schulz, Tak Mak, Julian Downward

Research output: Contribution to journalArticle

298 Citations (Scopus)

Abstract

The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster.
Original languageEnglish
Pages (from-to)9848-9862
Number of pages15
JournalMolecular and Cellular Biology
Volume24
Issue number22
DOIs
Publication statusPublished - Nov 2004

Keywords

  • Animals
  • Apoptosis
  • Base Sequence
  • Carrier Proteins
  • Corpus Striatum
  • DNA
  • Female
  • Gene Targeting
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria
  • Mitochondrial Proteins
  • Neurons
  • Parkinsonian Disorders
  • Phenotype
  • Pregnancy
  • Proteins
  • Serine Endopeptidases
  • X-Linked Inhibitor of Apoptosis Protein

Cite this

Martins, L. M., Morrison, A., Klupsch, K., Fedele, V., Moisoi, N., Teismann, P., ... Downward, J. (2004). Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Molecular and Cellular Biology, 24(22), 9848-9862. https://doi.org/10.1128/MCB.24.22.9848-9862.2004

Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. / Martins, L Miguel; Morrison, Alastair; Klupsch, Kristina; Fedele, Valentina; Moisoi, Nicoleta; Teismann, Peter; Abuin, Alejandro; Grau, Evelyn; Geppert, Martin; Livi, George P; Creasy, Caretha L; Martin, Alison; Hargreaves, Iain; Heales, Simon J; Okada, Hitoshi; Brandner, Sebastian; Schulz, Jörg B; Mak, Tak; Downward, Julian.

In: Molecular and Cellular Biology, Vol. 24, No. 22, 11.2004, p. 9848-9862.

Research output: Contribution to journalArticle

Martins, LM, Morrison, A, Klupsch, K, Fedele, V, Moisoi, N, Teismann, P, Abuin, A, Grau, E, Geppert, M, Livi, GP, Creasy, CL, Martin, A, Hargreaves, I, Heales, SJ, Okada, H, Brandner, S, Schulz, JB, Mak, T & Downward, J 2004, 'Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice', Molecular and Cellular Biology, vol. 24, no. 22, pp. 9848-9862. https://doi.org/10.1128/MCB.24.22.9848-9862.2004
Martins, L Miguel ; Morrison, Alastair ; Klupsch, Kristina ; Fedele, Valentina ; Moisoi, Nicoleta ; Teismann, Peter ; Abuin, Alejandro ; Grau, Evelyn ; Geppert, Martin ; Livi, George P ; Creasy, Caretha L ; Martin, Alison ; Hargreaves, Iain ; Heales, Simon J ; Okada, Hitoshi ; Brandner, Sebastian ; Schulz, Jörg B ; Mak, Tak ; Downward, Julian. / Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. In: Molecular and Cellular Biology. 2004 ; Vol. 24, No. 22. pp. 9848-9862.
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AU - Martins, L Miguel

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AU - Fedele, Valentina

AU - Moisoi, Nicoleta

AU - Teismann, Peter

AU - Abuin, Alejandro

AU - Grau, Evelyn

AU - Geppert, Martin

AU - Livi, George P

AU - Creasy, Caretha L

AU - Martin, Alison

AU - Hargreaves, Iain

AU - Heales, Simon J

AU - Okada, Hitoshi

AU - Brandner, Sebastian

AU - Schulz, Jörg B

AU - Mak, Tak

AU - Downward, Julian

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AB - The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster.

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KW - Parkinsonian Disorders

KW - Phenotype

KW - Pregnancy

KW - Proteins

KW - Serine Endopeptidases

KW - X-Linked Inhibitor of Apoptosis Protein

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DO - 10.1128/MCB.24.22.9848-9862.2004

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JO - Molecular and Cellular Biology

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