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Molecular and Cellular Biology, November 2004, p. 9848-9862, Vol. 24, No. 22
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.22.9848-9862.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Neuroprotective Role of the Reaper-Related Serine Protease HtrA2/Omi Revealed by Targeted Deletion in Mice

L. Miguel Martins,1,2 Alastair Morrison,3 Kristina Klupsch,1 Valentina Fedele,2 Nicoleta Moisoi,2 Peter Teismann,4 Alejandro Abuin,3 Evelyn Grau,3 Martin Geppert,3 George P. Livi,5 Caretha L. Creasy,5 Alison Martin,1 Iain Hargreaves,6 Simon J. Heales,6 Hitoshi Okada,7 Sebastian Brandner,8 Jörg B. Schulz,4 Tak Mak,7 and Julian Downward1*

Signal Transduction Laboratory, Cancer Research UK London Research Institute,1 Neurometabolic Unit,6 Division of Neuropathology and Department of Neurodegenerative Disease,8 Institute of Neurology, London, Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester,2 Department of Comparative Genomics, GlaxoSmithKline, Harlow, Essex, United Kingdom,3 Department of Comparative Genomics, GlaxoSmithKline, Upper Providence, Philadelphia, Pennsylvania,5 Department of Neurodegeneration and Neurorestoration, Center of Neurology and Center of Molecular Physiology of the Brain, University of Göttingen, Göttingen, Germany,4 Division of Cellular and Molecular Biology, AMDI Institute, Toronto, Ontario, Canada7

Received 4 August 2004/ Accepted 10 August 2004

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.

* Corresponding author. Mailing address: Cancer Research UK London Research Institute, Signal Transduction Laboratory, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 44-20-7269-3533. Fax: 44-20-7269-3094. E-mail: julian.downward{at}cancer.org.uk.

Molecular and Cellular Biology, November 2004, p. 9848-9862, Vol. 24, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.22.9848-9862.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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