ライフサイエンスコーパス: HTRA2

1 and Hid) and in mammals (Smac/DIABLO and Omi/Htra2).

2 and in mammalian cells (Smac/DIABLO and Omi/HtrA2).

3 e activation of the protease activity of Omi/HtrA2.

4 inhibitor of the proteolytic activity of Omi/HtrA2.

5 by inhibition of the mitochondrial protease HtrA2.

6 DZ domain and induces protease activation of HtrA2.

7 eracts with high temperature requirement A2 (HtrA2), a serine protease with a critical role in apopto

8 sm by which the mitochondrially released Omi/HtrA2 activates caspases during apoptosis.

9 This mechanism of Omi/HtrA2 activation is similar to the mechanism of activati

10 st, in MCF-7 lysates containing Smac and Omi/HtrA2, active caspase-7 is released from the apoptosome

11 Ablation of HtrA2 activity either by chemical inhibitor or by siRNA

12 In vitro studies have suggested that Omi/HtrA2 acts downstream of PINK1, mutations in which media

13 nd may regulate the protease activity of Omi/HtrA2 after its release from the mitochondria during apo

14 al protease high-temperature requirement A2 (HtrA2; also known as Omi) and prevents Ras-driven invasi

15 e optimal substrate sequence for cleavage by HtrA2 and also the preferred binding sequence for its PD

16 GRIM-19 physically interacts with HtrA2 and augments cell death in an IFN/all-trans retino

17 of APP and increased association of APP with HtrA2 and Derlin-1 in microsomal membranes.

18 ion peptide ligand for the PDZ domain of Omi/HtrA2 and may regulate the protease activity of Omi/HtrA

19 demiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results.

20 HTRA2 and PINK1 loss of function causes parkinsonism in

21 TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and

22 and suggesting that TRAP1 acts downstream of HTRA2 and PINK1.

23 imilar to that in Drosophila, which involves HTRA2 and subsequent inhibition of CIAP1 by cleavage.

24 nsfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A14

25 ucf-101 showed specific activity against Omi/HtrA2 and very little activity against various other ser

26 levels of cytochrome c, Smac/Diablo and Omi/HtrA2, and activation of caspases -3 and -9.

27 he release of cytochrome c, Smac/DIABLO, Omi/HtrA2, and AIF but not endonuclease G.

28 e (proteolytically processed) forms of Smac, HtrA2, and caspase-9.

29 s three putative HtrA-like proteases, HtrA1, HtrA2, and HtrA3.

30 demonstrate that IAPs are substrates for Omi/HtrA2, and their degradation could be a mechanism by whi

31 In cells lacking HtrA2, APP holoprotein is stabilized and accumulates in

32 hese results we suggest a novel function for HtrA2 as a regulator of APP metabolism through ER-associ

33 Here, we identify the serine protease HtrA2 as a WT1 binding partner and find that it cleaves

34 hybrid screen and identified serine protease HtrA2 as its binding partner.

35 patients, leading to the designation of Omi/HtrA2 as PD locus 13 (PARK13).

36 In the absence of the hTra2 beta 1 binding site, SRp30c failed to complex with

37 nt expression of an SR-like splicing factor, hTra2 beta 1, stimulates inclusion of exon 7 in SMN2-der

38 tivity required the same AG-rich enhancer as hTra2 beta 1.

39 er was mediated by a direct interaction with hTra2 beta 1.

40 omain of RNPS1 interact with p54, pinin, and hTra2 beta, respectively.

41 R protein family), human transformer 2 beta (hTra2 beta; an exonic splicing enhancer-binding protein)

42 of ITGA7 increases the protease activity of HtrA2 both in vitro and in vivo.

43 t, ectopic expression of mature wildtype Omi/HtrA2, but not an active site mutant, induces potent cas

44 egradation of XIAP, while suppression of Omi/HtrA2 by RNA interference has an opposite effect.

45 Suppression of Omi/HtrA2 by RNA interference in human cell lines reduces ce

46 Biochemical analysis reveals that HtrA2 can function both as a protease and as a chaperone

47 Proteolysis of WT1 by HtrA2 causes the removal of WT1 from its binding sites a

48 metric anti-IAP activity by Smac/DIABLO, Omi/HtrA2 cleavage of c-IAP1 is catalytic and irreversible,

49 HtrA2 coimmunoprecipitates exclusively with immature APP

50 ns significant, if not full, function of Omi/HtrA2, compared with expression of protease-compromised

51 fusion significantly increased cytosolic Omi/HtrA2 content and markedly increased apoptosis.

52 In vitro assays demonstrated that Omi/HtrA2 could degrade inhibitor of apoptosis proteins (IAP

53 ough PI3K/Akt activation, which prevents the HtrA2-dependent loss of XIAP.

54 beta-casein and induces cell death in an Omi/HtrA2-dependent manner.

55 y proteasomes and/or cleaved by caspases and HtrA2 depending on the specific stimulus and the cell ty

56 The three-dimensional structure of HtrA2 determined at 2.0 A resolution shows that the prot

57 Here, we demonstrate that Omi/HtrA2 directly cleaves various IAPs in vitro, and the cl

58 After specific HtrA2 downregulation, increased cell viability was measu

59 ctivity of ITGA7, whereas down-regulation of HtrA2 dramatically reduced cell death mediated by ITGA7.

60 In the presence of GRIM-19, the HtrA2-driven destruction of the antiapoptotic protein X-

61 HTRA2 encodes a mitochondrial serine protease.

62 ation determines whether the serine protease HtrA2 exerts pro- or antiapoptotic functions.

63 show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss

64 tion inhibitor, blocked translocation of Omi/HtrA2 from mitochondrial to cytoplasm, and protected tra

65 not provide support for models in which Omi/HtrA2 functions in the same genetic pathway as pink1, or

66 Furthermore, Omi/HtrA2 G399S retains significant, if not full, function o

67 a mutation in the mitochondrial protease Omi/HtrA2, G399S, was found in sporadic Parkinson's disease

68 we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients.

69 3 protein increases the transcription of the HTRA2 gene, which encodes a serine protease that interac

70 The deletion of htrA2 gives attenuated virulence in a mouse model of TB.

71 Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a pa

72 The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in

73 l (presenilin-associated, rhomboid-like) and HtrA2 (high-temperature-regulated A2, also known as Omi)

74 These data show a critical role of HtrA2 in a cytokine-induced cell death response for the

75 we analyzed the entire coding region of OMI/HTRA2 in a series of 644 North American PD cases with bo

76 his observation, increased expression of Omi/HtrA2 in cells increases degradation of XIAP, while supp

77 or stably overexpression of mitochondria Omi/HtrA2 in H9C2 cells enhance apoptosis as evidenced by el

78 cribed direct interaction between Mpv17l and HtrA2 in mitochondria.

79 apoptogenic proteins cytochrome c, Smac, and HtrA2 in response to Bim.

80 However, the role of Omi/HtrA2 in the apoptotic cell death that occurs in vivo un

81 accumulations of cytochrome c, Smac, and Omi/HtrA2 in the cytosol and induced the poly(ADP-ribose) po

82 accumulation of cytochrome c, Smac, and Omi/HtrA2 in the cytosol; and inhibited the processing and a

83 ndings provide insights into the function of HtrA2 in the regulation of apoptosis and the oncogenic a

84 -terminal PDZ binding motif, potentiated Omi/HtrA2-induced cell death.

85 ) null fibroblasts, was found to inhibit Omi/HtrA2-induced cell death.

86 in vivo overexpression of mitochondrial Omi/HtrA2 induces cardiac apoptosis and dysfunction.

87 Omi/HtrA2 induces cell death in a caspase-dependent manner b

88 vehicle or ucf-101, a novel and specific Omi/HtrA2 inhibitor, 10 minutes before reperfusion.

89 ompletely blocked by Ucf-101, a specific Omi/HtrA2 inhibitor.

90 HtrA2 inhibits mitochondrial superoxide generation, stab

91 Deletion of the HtrA2 interaction domain abrogates the cell death activi

92 elease of cytochrome c, Smac/Diablo, and Omi/HtrA2 into the cytosol; caspase-3 activation; and apopto

93 Omi/HtrA2 is a mammalian serine protease with high homology

94 Omi/HtrA2 is a mitochondrial serine protease that is release

95 Human HtrA2 is a novel member of the HtrA serine protease fami

96 Omi/HtrA2 is a nuclear-encoded mitochondrial serine protease

97 Omi/HtrA2 is a proapoptotic mitochondrial serine protease in

98 Omi/HtrA2 is localized in mitochondria and is released to th

99 The mature serine protease Omi/HtrA2 is released from the mitochondria into the cytosol

100 , a fly homologue of the serine protease Omi/HtrA2, is a developmentally regulated mitochondrial inte

101 is-dependent cleavage of WT1 is defective in HtrA2 knockout cells.

102 A subpopulation of HtrA2 localizes to the cytosolic side of the endoplasmic

103 ous mutation and a novel polymorphism in OMI/HTRA2 locus have been associated with Parkinson's diseas

104 acterized proapoptotic function of cytosolic HtrA2, mechanisms underlying the mitochondrial protectiv

105 oth protease and PDZ binding pockets of each HtrA2 molecule are occupied by autoproteolytic peptide p

106 Here, we show that Omi/HtrA2 null mutants in Drosophila, in contrast to pink1 o

107 HtrA2/Omi and caspase-3 expression was evaluated using R

108 Smac/Diablo and HtrA2/Omi are inhibitors of apoptosis (IAP)-binding prot

109 The cell death-promoting properties of HtrA2/Omi are not only exerted through its capacity to o

110 the release of cytochrome c, Smac/Diablo and HtrA2/Omi but not endonuclease G (EndoG) and apoptosis-i

111 However, the regulation of HtrA2/Omi by signaling molecule has not been documented.

112 The function of HtrA2/Omi closely relates to its protease activity, whic

113 otype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25.

114 HtrA2/Omi expression in the subcellular components and a

115 Furthermore, the phosphorylated HtrA2/Omi fails to cleave X-linked inhibitor of apoptoti

116 ic switch are conserved in the DegP/HtrA and HtrA2/Omi families, suggesting that many PDZ proteases u

117 ve of p53 expression, causing the release of HtrA2/Omi from mitochondria into the cytosol.

118 In addition, Akt inhibits the release of HtrA2/Omi from the mitochondria into the cytoplasm in re

119 The serine protease HtrA2/Omi has an amino-terminal IAP interaction motif li

120 Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by

121 evaluated in cells treated with UCF-101, an HtrA2/Omi inhibitor or in cells subjected to RNAi agains

122 These data reveal for the first time that HtrA2/Omi is directly regulated by Akt and provide a mec

123 These findings suggest that HtrA2/Omi is related to RPE apoptosis due to oxidative s

124 When HtrA2/Omi is released from mitochondria following an apo

125 The serine protease HtrA2/Omi is released from the mitochondria into the cyt

126 The serine protease HtrA2/Omi is released from the mitochondrial intermembra

127 Mammalian HtrA2/Omi is therefore likely to function in vivo in a m

128 O, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them.

129 fy WT1 as a novel bona fide substrate of the HtrA2/Omi mitochondrial protease and show that this reac

130 and Akt2 phosphorylate mitochondria-released HtrA2/Omi on serine 212 in vivo and in vitro, which resu

131 Abolishing HtrA2/Omi phosphorylation by Akt through mutation of ser

132 ptosis protein (XIAP) to the Reaper motif of HtrA2/Omi results in a marked increase in proteolytic ac

133 ese peptides, we show that the PDZ domain of HtrA2/Omi suppresses the proteolytic activity unless it

134 Phosphorylated HtrA2/Omi therefore cleaves beta-actin and decreases the

135 This, together with the ability of HtrA2/Omi to degrade IAPs, may limit the overall cellula

136 Subjecting HtrA2/Omi to heat shock treatment also increases its pro

137 (2)O(2)-induced oxidative damage resulted in HtrA2/Omi translocation from mitochondria to cytosol, le

138 ewer and abnormal mitochondria were found in HtrA2/Omi(-)(/)(-) photoreceptors and RPE.

139 optosis-inducing factor, endonuclease G, and HtrA2/Omi).

140 e yeast two-hybrid assay, here we identified HtrA2/Omi, a stress-responsive chaperone-protease as a p

141 ed the release of cytochrome c, Smac/DIABLO, HtrA2/Omi, and AIF from the mitochondria and down-regula

142 Smac/DIABLO, HtrA2/Omi, and caspase-9 play key roles in the initiatio

143 F-101 reduced the cytosolic translocation of HtrA2/Omi, attenuated caspase-3 activation, and decrease

144 the efflux of cytochrome c, Smac/Diablo and HtrA2/Omi, but both prevented the release of EndoG and A

145 ttlerin induced the release of cytochrome c, HtrA2/Omi, Smac/DIABLO, and AIF from the mitochondria, p

146 vity of the serine proteases, granzyme B and HtrA2/Omi, to avoid cell death.

147 ed to view the retinal ultrastructure of the HtrA2/Omi-deficient mice.

148 vation, it could have the opposite effect on HtrA2/Omi-dependent cell death.

149 t through mutation of serine 212 to alanine (HtrA2/Omi-S212A) retains its serine protease activity an

150 Conversely, HtrA2/Omi-S212D, a mutant mimicking phosphorylation, los

151 es more apoptosis as compared with wild-type HtrA2/Omi.

152 mitochondria and induces phosphorylation of HtrA2/Omi.

153 creased oxidative stress and upregulation of HtrA2/Omi.

154 ibitor or in cells subjected to RNAi against HtrA2/Omi.

155 Mutations in HTRA2/Omi/PARK13 have been implicated in Parkinson disea

156 mitochondria-specific, not cytoplasmic, Omi/HtrA2 on myocardial apoptosis and cardiac function.

157 Thus, strategies to directly inhibit Omi/HtrA2 or its cytosolic translocation from mitochondria m

158 ibition of ER-associated degradation (either HtrA2 or proteasome) promotes binding of APP to the COPI

159 chondrial serine protease Omi (also known as HtrA2 or Prss25).

160 chanistic studies revealed mitochondrial Omi/HtrA2 overexpression degraded the mitochondrial anti-apo

161 equencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both

162 Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tr

163 Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other popu

164 HTRA2 p.G399S was previously shown to lead to mitochondr

165 s, we do not favor a hypothesis in which Omi/HtrA2 plays an essential role in PD pathogenesis, at lea

166 tudy was designed to investigate whether Omi/HtrA2 plays an important role in postischemic myocardial

167 mouse lymphocytes, the presence of processed HtrA2 prevents the accumulation of mitochondrial-outer-m

168 levels, but TRAP1 is not a direct target of HTRA2 protease activity.

169 unique interacting protein and regulator of HtrA2 protease mediating antioxidant and antiapoptotic f

170 Whether Omi/HtrA2 regulates mitochondrial integrity and whether it a

171 HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a

172 esults indicate that unlike Smac/DIABLO, Omi/HtrA2's catalytic cleavage of IAPs is a key mechanism fo

173 is specific to HtrA1, as similar assays with HtrA2 showed minimal ApoE4 proteolysis and trypsin had n

174 ers (ESEs), including motifs associated with hTra2, SRp55, and SRp20, evolved in a compensatory manne

175 teolytic activity of the serine protease Omi/HtrA2 through direct interaction with its regulatory PDZ

176 These interactions allow Hax1 to present HtrA2 to Parl, and thereby facilitates the processing of

177 l, and thereby facilitates the processing of HtrA2 to the active protease localized in the mitochondr

178 ly increases the proteolytic activity of Omi/HtrA2 toward the inhibitor of apoptosis proteins and bet

179 ime that ischemia/reperfusion results in Omi/HtrA2 translocation from the mitochondria to the cytosol

180 antly elevated expression of cytoplasmic Omi/HtrA2, triggers cardiomyocytes apoptosis.

181 ere, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach.

182 Loss of function of HtrA2 was previously shown to lead to parkinsonian featu

183 he mature serine protease Omi (also known as HtrA2) was identified as a mitochondrial direct BIR3-bin

184 xpressing cardiac-specific mitochondrial Omi/HtrA2 were generated and they had increased myocardial a

185 ected cells overexpressing mitochondrial Omi/HtrA2 were more sensitive to hypoxia and reoxygenation (

186 Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death

187 However, whether increased Omi/HtrA2 within mitochondria itself influences myocardial s

188 s containing very low levels of Smac and Omi/HtrA2, XIAP (X-linked inhibitor of apoptosis) binds tigh