Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice.
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.
Martins
L Miguel
LM
Signal Transduction Laboratory, Cancer Research UK London Research Institute, United Kingdom.
Morrison
Alastair
A
Klupsch
Kristina
K
Fedele
Valentina
V
Moisoi
Nicoleta
N
Teismann
Peter
P
Abuin
Alejandro
A
Grau
Evelyn
E
Geppert
Martin
M
Livi
George P
GP
Creasy
Caretha L
CL
Martin
Alison
A
Hargreaves
Iain
I
Heales
Simon J
SJ
Okada
Hitoshi
H
Brandner
Sebastian
S
Schulz
Jörg B
JB
Mak
Tak
T
Downward
Julian
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D003342:Corpus Striatum / Q000002:abnormalities / Q000196:embryology* / Q000201:enzymology*; D004247:DNA / Q000235:genetics; D005260:Female; D018390:Gene Targeting; D000074923:High-Temperature Requirement A Serine Peptidase 2; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000473:pathology; D020734:Parkinsonian Disorders / Q000196:embryology / Q000209:etiology / Q000235:genetics; D010641:Phenotype; D011247:Pregnancy; D011506:Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D024101:Mitochondrial Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D004247:DNA; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse