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 erived proapoptotic factors such as SMAC and HTRA2.

6 by inhibition of the mitochondrial protease HtrA2.

7 DZ domain and induces protease activation of HtrA2.

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

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

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

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

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

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

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

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

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

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

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

19 eover, grafting the HTRA1-LoopA epitope onto HTRA2 and HTRA3 transferred the allosteric inhibition me

20 e with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import

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

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

23 HTRA2 and PINK1 loss of function causes parkinsonism in

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

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

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

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

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

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

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

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

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

33 embrane space proteins including CLPB, HAX1, HTRA2, and the inner membrane quality control proteins (

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

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

36 and inactivating mutations to mitochondrial HTRA2 are implicated in PD.

37 Our data paint a picture of HtrA2 as a finely tuned, stress-protective enzyme whose

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

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

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

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

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

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

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

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

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

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

48 ceptor kinase (drk) with an added C-terminal HtrA2-binding motif (drkN SH3-PDZbm) that exhibits margi

49 However, very little is known about how HtrA2 binds to protein substrates and if the distinct co

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

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

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

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

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

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

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

57 HtrA2 coimmunoprecipitates exclusively with immature APP

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

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

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

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

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

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

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

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

66 After specific HtrA2 downregulation, increased cell viability was measu

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

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

69 HTRA2 encodes a mitochondrial serine protease.

70 In the absence of substrates, HtrA2 exchanges between a heretofore unobserved hexameri

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

72 upregulated high temperature requirement A2 (HtrA2) expression to promote apoptosis while decreasing

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

74 HtrA2 forms a homotrimeric structure, with each subunit

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

76 ulating cell-signaling events, with aberrant HtrA2 function leading to neurodegeneration and parkinso

77 ole of interprotomer allostery in regulating HtrA2 function.

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

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

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

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

82 3 protein increases the transcription of the HTRA2 gene, which encodes a serine protease that interac

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

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

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

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

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

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

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

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

91 cribed direct interaction between Mpv17l and HtrA2 in mitochondria.

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

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

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

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

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

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

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

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

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

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

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

103 HtrA2 inhibits mitochondrial superoxide generation, stab

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

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

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

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

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

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

110 Omi/HtrA2 is a proapoptotic mitochondrial serine protease in

111 ous aggregates, and the aberrant function of HtrA2 is closely related to the onset of neurodegenerati

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

113 In this manner, wild-type HtrA2 is only active when substrate concentrations are h

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

115 Human High temperature requirement A2 (HtrA2) is a mitochondrial protease chaperone that plays

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

117 Other top models were the mitochondrial gene HTRA2 knockout (that is lethal in adulthood), a modified

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

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

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

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

122 The human high-temperature requirement A2 (HtrA2) mitochondrial protease is critical for cellular p

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

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

125 oncert with biochemical assays, a functional HtrA2 oligomerization/binding cycle has been established

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

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

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

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

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

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

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

133 HtrA2/Omi expression in the subcellular components and a

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

166 pro-apoptotic cytochrome c, SMAC/DIABLO, and HTRA2/OMI, which promoted caspase-9 and -3 activation.

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

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

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

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

171 ules, including clusterin, cytochrome C, and HTRA2/OMI.

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

173 mitochondria and induces phosphorylation of HtrA2/Omi.

174 creased oxidative stress and upregulation of HtrA2/Omi.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

191 The human high-temperature requirement A2 (HtrA2) protein is a trimeric protease that cleaves misfo

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

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

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

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

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

197 ficantly stimulate the catalytic activity of HtrA2, suggesting that binding avidity plays an importan

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

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

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

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

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

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

204 actions between several clients and a single HtrA2 trimer significantly stimulate the catalytic activ

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

206 We show that drkN SH3-PDZbm binds to HtrA2 via a two-pronged interaction, involving both its

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

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

209 otein 6 (BIRC6) bound to SMAC, caspases, and HTRA2, we provide a molecular understanding for BIRC6-me

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

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

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

213 structural description of the interaction of HtrA2 with protein substrates and highlight the importan

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

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