ライフサイエンスコーパス: eIF2alpha

1 eIF2alpha phosphorylation-mediated translational regulat

2 eIF2alpha-D1 is mainly inserted between the N-terminal h

3 c translation initiation factor 2 subunit 1 (eIF2alpha), the SG assembly G3BP paralogs, or release of

4 eukaryotic translation initiation factor 2 (eIF2alpha) resulting in inhibition of general protein sy

5 rylation of translation initiation factor 2 (eIF2alpha) terminates signalling in the mammalian integr

6 eukaryotic translation initiation factor 2 (eIF2alpha) was decreased, and host protein synthesis was

7 a subunit of eukaryotic initiation factor 2 (eIF2alpha).

8 a subunit of eukaryotic initiation factor 2 (eIF2alpha).

9 ryotic translation initiation factor 2alpha (eIF2alpha) and regulated expressions of autophagy marker

10 ion of translation initiation factor 2alpha (eIF2alpha) attenuates global protein synthesis but enhan

11 tion of eukaryotic initiation factor 2alpha (eIF2alpha) controls transcriptome-wide changes in mRNA t

12 ryotic translation initiation factor 2alpha (eIF2alpha) kinase GCN2 is activated by amino acid starva

13 ryotic translation initiation factor 2alpha (eIF2alpha) mouse embryonic fibroblasts (MEFs); moreover,

14 olonged eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation, leading to a proteostatic re

15 ryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation-dependent integrated stress r

16 ryotic translation initiation factor 2alpha (eIF2alpha) results in the induction of the transcription

17 rylates eukaryotic initiation factor 2alpha (eIF2alpha) to attenuate global translation, thus reducin

18 te the translation initiation factor 2alpha (eIF2alpha) to prevent host translational shutoff.

19 quiring eukaryotic initiation factor 2alpha (eIF2alpha), the transcription factor ATF4, and the heat

20 tion of eukaryotic initiation factor 2alpha (eIF2alpha), with deletions of eIF2alpha kinases or treat

21 arasite eukaryotic initiation factor-2alpha (eIF2alpha), leading to repression of general translation

22 The results show lipid-activated eIF2alpha signaling induces a mitochondrial protease, Lo

23 ntrols mitochondrial clearance by activating eIF2alpha-LONP1 signaling, contributing to an amplified

24 te in PKR binding, pTRS1 bound an additional eIF2alpha kinase, heme-regulated inhibitor (HRI), and in

25 ts of the regulated genes include additional eIF2alpha kinase Hri2 amplifying the stress signaling an

26 ion on eukaryotic initiation factor 2 alpha (eIF2alpha) and activate the integrated stress response (

27 ng the eukaryotic initiation factor 2 alpha (eIF2alpha) or other signal transduction cascades.

28 yotic translation initiation factor 2 alpha (eIF2alpha), in vitro and in breast cancer cells.

29 yotic translation initiation factor 2 alpha (eIF2alpha), which orchestrates the cellular stress respo

30 yotic translation initiation factor 2 alpha (eIF2alpha).

31 yotic translation initiation factor 2 alpha (eIF2alpha).

32 n factor initiation elongation factor alpha (eIF2alpha).

33 anslation initiation factor 2 subunit alpha (eIF2alpha), causing inhibition of mRNA translation and s

34 s have been attributed to its function as an eIF2alpha kinase.

35 ription is mediated at least partially by an eIF2alpha-dependent increase in ATF4 expression.

36 ISR-enhanced RAN translation requires an eIF2alpha phosphorylation-dependent alteration in start

37 tion of OLA1 expression or treatment with an eIF2alpha dephosphorylation inhibitor, suggesting that O

38 rk, their downstream effectors Grp78/BiP and eIF2alpha in ERG transgenic mouse prostate glands indica

39 translation initiation factor 4F (eIF4F) and eIF2alpha pathways, whereas the pathways regulating SG d

40 sensor PERK (protein kinase-like kinase) and eIF2alpha-ATF4-CHOP signaling.

41 terestingly, FAM129A regulated both PERK and eIF2alpha in a feedback loop that differentially channel

42 In addition, both PKR and eIF2alpha were phosphorylated during infection when pTRS

43 osphatase 1 catalytic subunit (PP1alpha) and eIF2alpha to assemble a phosphatase complex catalyzing e

44 e interface between 40S protein Rps5/uS7 and eIF2alpha between open and closed states; however, its i

45 red a potential regulatory interplay between eIF2alpha arginine methylation by PRMT7 and stress-induc

46 T1B and unveil a possible cross talk between eIF2alpha and the MEK/ERK pathway in neuropathic nerves.

47 Recently, both eIF2alpha and its kinases were found to play a role in n

48 s stress granule assembly that required both eIF2alpha phosphorylation and G3BP.

49 pression and phosphorylation of AKT, 4E-BP1, eIF2alpha, AMPKalpha, p70 S6 kinase and rpS6 in muscle h

50 gonize translational reprogramming caused by eIF2alpha phosphorylation (e.g. ISRIB), suggesting that

51 ation of eIF2alpha, surprisingly mediated by eIF2alpha kinase 1, or heme-regulated kinase inhibitor (

52 steps in translation initiation regulated by eIF2alpha phosphorylation and the mTOR/4E-BP pathway, re

53 ism for these critical adaptive responses by eIF2alpha-P involved induced expression of CDKN1A encodi

54 ty of a translation initiation factor called eIF2alpha might be partly responsible for the increased

55 to assemble a phosphatase complex catalyzing eIF2alpha dephosphorylation and resumption of protein sy

56 amino acid point mutations in the conserved eIF2alpha binding domain of PKR disrupted pTRS1 binding

57 stent with a critical role for the conserved eIF2alpha contact site in PKR binding, pTRS1 bound an ad

58 In contrast, eIF2alpha-R53 interacts with the rRNA backbone only in t

59 ctivated protein kinase (PKR) also decreased eIF2alpha phosphorylation, the translation of viral stru

60 Mice with decreased eIF2alpha phosphorylation (eIF2alpha(+/S51A)) exhibit re

61 h P-stalk lesions, stimulated GCN2-dependent eIF2alpha phosphorylation in vitro.

62 phosphatase 1 complex that dephosphorylates eIF2alpha.

63 A family of different eIF2alpha kinases function in the integrative stress res

64 uS7 substitutions disrupting eIF2alpha contacts favored in the open complex increase

65 diated translation control mechanisms during eIF2alpha-P and additionally illustrate the roles that p

66 t evidence for a key role of a dysfunctional eIF2alpha pathway in the pathogenesis of dystonia.

67 hosphorylation of the alpha subunit of eIF2 (eIF2alpha-P) represses global protein synthesis, coincid

68 hosphorylation of the alpha subunit of eIF2 (eIF2alpha-P), which represses translation initiation and

69 ranslation initiation factor 2alpha (EIF2AK2/eIF2alpha) axis as a major pathway in mediating septic A

70 n through GCN2 phosphorylation of eIF2alpha (eIF2alpha-P).

71 to encode a non-phosphorylatable eIF2alpha (eIF2alpha(S51A)).

72 lic variability of the Eif2s1 gene (encoding eIF2alpha) on reward-related neuronal responses in human

73 ing pocket and the pockets that would engage eIF2alpha during active nucleotide exchange, thereby dis

74 phorylation of translation initiation factor eIF2alpha (alpha subunit of eukaryotic initiation factor

75 ylation of the translation initiation factor eIF2alpha (p-eIF2alpha) accounts for adolescent hypersen

76 ylation of the translation initiation factor eIF2alpha anchors a reversible regulatory switch that re

77 ylation of the translation initiation factor eIF2alpha via the unfolded protein response (UPR) kinase

78 ylation of the translation initiation factor eIF2alpha within the mediobasal hypothalamus is known to

79 s phosphorylate eukaryotic initiation factor eIF2alpha, enabling the translation of stress response g

80 phosphorylates translation initiation factor eIF2alpha, initiating the integrated stress response (IS

81 e PERK and the translation initiation factor eIF2alpha, is a pathological feature of many neurodegene

82 phorylation of translation initiation factor eIF2alpha, which promotes the formation of discrete cyto

83 ylation of the translation initiation factor eIF2alpha.

84 phosphorylation of mRNA translational factor eIF2alpha and its kinase PERK.

85 ive GCN2 kinase is the only known kinase for eIF2alpha serine 56 in Arabidopsis (Arabidopsis thaliana

86 In this study, we elucidated a mechanism for eIF2alpha-P cytoprotection in response to UVB in human k

87 , we demonstrated that PRMT7 is required for eIF2alpha-dependent stress granule formation in the face

88 Furthermore, eIF2alpha-P dephosphorylation, assessed by a kinase shut

89 xcess light conditions, implicating the GCN2-eIF2alpha pathway in responses to light and associated R

90 The GCN2-eIF2alpha signaling pathway is specifically activated by

91 nscription, as well as the conventional Gcn2/eIF2alpha-mediated increased translation of Gcn4.

92 We propose that HRI, eIF2alpha, and HSPB8 define a novel cytosolic unfolded p

93 The HRI/eIF2alpha signaling axis was also essential for signalin

94 In this issue, Tsuyama et al. identify eIF2alpha phosphorylation as a critical regulator of mit

95 w that in addition to turning off the immune/eIF2alpha phosphorylation-dependent inhibition of transl

96 rsely, long-term stress led to a decrease in eIF2alpha (Ser51) phosphorylation and ATF4 expression an

97 The H2S-induced increase in eIF2alpha phosphorylation was mediated at least in part

98 e levels are so low; HRI activity results in eIF2alpha phosphorylation and the resulting inhibition o

99 Different pathways including eIF2alpha, 4EBP, and S6K1 signaling contribute to contro

100 Increased eIF2alpha phosphorylation shortens the circadian period

101 anical, pain sensitivity, whereas increasing eIF2alpha phosphorylation has the opposite effect on the

102 Induced eIF2alpha phosphorylation by the general control nondere

103 ART-induced eIF2alpha phosphorylation is mediated by the Plasmodium

104 t to canonical UPR signaling, Sema3A-induced eIF2alpha phosphorylation bypasses global translational

105 entially translated following stress-induced eIF2alpha-P by a mechanism mediated in part by upstream

106 cient in active PPP1R15A, a stress-inducible eIF2alpha phosphatase, are healthy and more resistant to

107 ific, as LCMV is unable to similarly inhibit eIF2alpha phosphorylation.

108 eme-regulated inhibitor (HRI), and inhibited eIF2alpha phosphorylation in response to an HRI agonist.

109 recrudescence following ART, and inhibiting eIF2alpha dephosphorylation renders parasites less sensi

110 Moreover, selectively inhibiting eIF2alpha-mediated translational control with a small mo

111 The small molecule Sephin1 inhibits eIF2alpha dephosphorylation, thereby prolonging the prot

112 ndent upon a heme-regulated inhibitor kinase/eIF2alpha/activating transcription factor 4 (ATF4) signa

113 ined previously by their ability to maintain eIF2alpha phosphorylation by allosterically inhibiting p

114 gnition and hippocampal LTP by PERK-mediated eIF2alpha phosphorylation, providing molecular mechanism

115 oids, which demonstrates that a negative MYC-eIF2alpha feedback loop constitutes a targetable vulnera

116 rected oxidative stressor, in the absence of eIF2alpha phosphorylation suggest other roles for GADD34

117 al translation of its mRNA in the absence of eIF2alpha phosphorylation.

118 orsening of the neuropathy in the absence of eIF2alpha phosphorylation.

119 K inhibition may be linked to attenuation of eIF2alpha phosphorylation and reveals a previously unkno

120 Pharmacological attenuation of eIF2alpha phosphorylation decreases thermal, but not mec

121 s large rearrangements to promote binding of eIF2alpha to the regulatory core of eIF2B comprised of t

122 alpha and indirectly by inducing contacts of eIF2alpha helix 58-63 with eIF2Bdelta leading to a compe

123 Restoring translational control of eIF2alpha holds the promise to rejuvenate adult brain pl

124 factor 2alpha (eIF2alpha), with deletions of eIF2alpha kinases or treatment with eIF2alpha kinase inh

125 apable of mediating the dephosphorylation of eIF2alpha, and the virus was capable of controlling the

126 mplex that promotes the dephosphorylation of eIF2alpha, prolonged eIF2alpha phosphorylation and impro

127 protein phosphatase for dephosphorylation of eIF2alpha-P to restore protein synthesis.

128 involve GADD34-mediated dephosphorylation of eIF2alpha-P.

129 sponse is terminated by dephosphorylation of eIF2alpha.

130 required for ATF4 translation downstream of eIF2alpha phosphorylation.

131 canning on mRNAs leading to the formation of eIF2alpha-independent stress granules.

132 lular fractions; and greater inactivation of eIF2alpha, a major defensive step of the unfolded protei

133 Moreover, we show that induction of eIF2alpha phosphorylation in primary sensory neurons in

134 ion with GSK2606414A led to an inhibition of eIF2alpha phosphorylation, which correlated with reduced

135 sphorylation of eIF2alpha, and inhibition of eIF2alpha signaling activity suppressed CDCA regulation

136 reatment of P23H-1 rats with an inhibitor of eIF2alpha phosphatase, salubrinal, led to improved photo

137 optosis inducer, and GADD34, an inhibitor of eIF2alpha phosphorylation, demonstrated that PC1-5TMC in

138 Thus, distinct interactions of eIF2alpha with rRNA or mRNA stabilize first the open, an

139 S63del neuropathy, despite reduced levels of eIF2alpha phosphorylation (P-eIF2alpha).

140 uttling in a manner correlating to levels of eIF2alpha-P.

141 Loss of eIF2alpha-P induced by UVB diminished G1 arrest, DNA rep

142 dings implicate PRMT7 as a novel mediator of eIF2alpha-dependent cellular stress response pathways.

143 translation through GCN2 phosphorylation of eIF2alpha (eIF2alpha-P).

144 We show that inhibitory phosphorylation of eIF2alpha (P-eIF2alpha), a conserved translation initiat

145 Increased levels of phosphorylation of eIF2alpha (Ser51) were detected prior to neurodegenerati

146 ivity, an increase in the phosphorylation of eIF2alpha (Ser51), and an increase in the level of ATF4

147 stress response (ISR) via phosphorylation of eIF2alpha and the subsequent control of eukaryotic initi

148 unknown function for GCN2 phosphorylation of eIF2alpha and translational control in the formation of

149 Phosphorylation of eIF2alpha controls translation initiation by restricting

150 Mechanistically, phosphorylation of eIF2alpha promotes mRNA translation of Atf4.

151 and 2) an increase in the phosphorylation of eIF2alpha protein.

152 PERK-mediated phosphorylation of eIF2alpha requires its binding to the insert loop within

153 t PC1 and PC1-5TMC reduce phosphorylation of eIF2alpha through inhibiting PKR phosphorylation.

154 response is initiated by phosphorylation of eIF2alpha to diminish global protein translation and sel

155 PC-deficient cells induce phosphorylation of eIF2alpha via the kinases GCN2 and PKR.

156 EBP1, as well as elevated phosphorylation of eIF2alpha, an inhibitor of mRNA translation.

157 CDCA increased the phosphorylation of eIF2alpha, and inhibition of eIF2alpha signaling activit

158 chemical that inhibits de-phosphorylation of eIF2alpha, and it can suppress cell death from the ER st

159 Nonetheless, reducing phosphorylation of eIF2alpha, by Perk haploinsufficiency, also ameliorates

160 monitored by PKR-mediated phosphorylation of eIF2alpha, in fibroblasts from patients with EIF2AK2 var

161 n inhibition involved the phosphorylation of eIF2alpha, surprisingly mediated by eIF2alpha kinase 1,

162 ated stress response, via phosphorylation of eIF2alpha, thus linking these pathways.

163 ranslation initiation via phosphorylation of eIF2alpha.

164 deficits independently of phosphorylation of eIF2alpha.

165 through the elevation of phosphorylation of eIF2alpha.

166 closed complex between arginines R55/R57 of eIF2alpha with mRNA, including the -3 nucleotide of the

167 Reversal of eIF2alpha-mediated translational repression using ISRIB

168 ompted us to genetically explore the role of eIF2alpha phosphorylation in P0S63del-CMT1B neuropathy t

169 essed a nonphosphorylatable mutant (S51A) of eIF2alpha.

170 and stress-induced phosphorylation status of eIF2alpha at serine 51.

171 ort the notion that therapeutic targeting of eIF2alpha signaling could restrict tumor cell metastasis

172 ntegrated stress response (ISR) converges on eIF2alpha phosphorylation to regulate protein synthesis.

173 ant (C127S-PP1c) abrogated the H2S effect on eIF2alpha phosphorylation.

174 RNAi-mediated knockdown of PERK or eIF2alpha abrogated the endorepellin-mediated up-regulat

175 ion of RNA-dependent protein kinase (PKR) or eIF2alpha, indicating that L(pro) does not affect SG for

176 teraction between PPP1R15A and either PP1 or eIF2alpha in intact cells.

177 P-eIF2alpha inhibits eIF2B, the guanine nucleotide exchang

178 on of eukaryotic initiation factor 2alpha (p-eIF2alpha).

179 In accordance, p-eIF2alpha levels were significantly elevated in high-RNF

180 Thus, RNF4 and p-eIF2alpha establish a positive feed-forward loop connect

181 e levels of both phospho-PERK (p-PERK) and p-eIF2alpha, and these effects were enhanced upon ER stres

182 cological activation of eIF2B are tuned by P-eIF2alpha concentration.

183 an mRNA whose translation is controlled by p-eIF2alpha-in the VTA also prolongs cocaine-induced LTP.

184 ases, containing GADD34 and CReP, catalyze P-eIF2alpha dephosphorylation.

185 Cycling P-eIF2alpha levels required rhythmic activation of the eIF

186 sphorylation of the alpha-subunit of eIF2 (p-eIF2alpha), the central component of the integrated stre

187 e translation initiation factor eIF2alpha (p-eIF2alpha) accounts for adolescent hypersensitivity to c

188 d stabilizes the phosphorylated eIF2alpha (p-eIF2alpha) but not activating transcription factor 4 or

189 t inhibitory phosphorylation of eIF2alpha (P-eIF2alpha), a conserved translation initiation factor, i

190 th genetic or pharmacological reduction in p-eIF2alpha-mediated translation are more susceptible to n

191 stress signaling associated with increased p-eIF2alpha and ATF4 and decreased sXBP1 and CHOP.

192 able to inhibit the ISR when intracellular P-eIF2alpha concentrations exceed a critical threshold lev

193 Trehalose increases pre-stress levels of p-eIF2alpha and its phosphatase subunits and promotes post

194 hat rescues translation in the presence of P-eIF2alpha by facilitating the assembly of more active eI

195 Moreover, ablation of p-eIF2alpha in either excitatory or somatostatin-expressin

196 Clock-controlled accumulation of P-eIF2alpha led to reduced translation during the day in v

197 of ECD led to marked decreases in p-PERK, p-eIF2alpha, and ATF4 levels but robust increases in GRP78

198 and p-Bad) and ER stress-related (p-PERK, p-eIF2alpha, ATF4 and CHOP) apoptotic pathways.

199 duced levels of eIF2alpha phosphorylation (P-eIF2alpha).

200 in both mice and humans, and that reduced p-eIF2alpha may enhance susceptibility to nicotine (and ot

201 e ISR kinases(14-17), or mimicking reduced p-eIF2alpha with the ISR inhibitor ISRIB(11), enhances lon

202 Finally, loss of rhythmic P-eIF2alpha levels led to reduced linear growth rates, sup

203 translationally controlled via the Sema3A-p-eIF2alpha pathway.

204 These findings suggest that p-eIF2alpha regulates synaptic actions of nicotine in both

205 ct of trehalose on SGs is mediated via the p-eIF2alpha rather than autophagosome pathway.

206 Our data support the targeting of the P-eIF2alpha/Gadd34 complex as a therapeutic avenue in CMT1

207 s were low, but not late in infection when P-eIF2alpha levels were high.

208 escued translation early in infection when P-eIF2alpha levels were low, but not late in infection whe

209 -associated proteins, including GRP78, PERK, eIF2alpha, ATF4, IRE1alpha, JNK, p38, and CHOP.

210 stress signaling pathway consisting of PERK, eIF2alpha, ATF4, and GADD45alpha.

211 M (mostly IRE1 driven) and T2DM (mostly PERK-eIF2alpha dependent).

212 at Thr(799) to partially down-regulate PERK-eIF2alpha signaling while avoiding widespread ISR inhibi

213 CLPP was negatively regulated by the PERK-eIF2alpha arm of the endoplasmic reticulum UPR pathway,

214 The PERK-eIF2alpha-ATF4 axis increases supercomplex assembly fact

215 that Leishmania parasites activate the PERK/eIF2alpha/ATF-4 pathway in cultured macrophages and infe

216 We report here that the PERK/eIF2alpha/ATF4 signaling branch of the integrated endopl

217 atforms, functionally homologous to the PERK/eIF2alpha/HSPA5 axis of the endoplasmic reticulum UPR.

218 st be tightly regulated; however, persistent eIF2alpha phosphorylation is observed in mouse and human

219 if2s1 locus to encode a non-phosphorylatable eIF2alpha (eIF2alpha(S51A)).

220 ated during heme deficiency to phosphorylate eIF2alpha (eIF2alphaP), which simultaneously inhibits th

221 rerequisite for its ability to phosphorylate eIF2alpha, is readily induced by JUNV.

222 Es), which did not accumulate phosphorylated eIF2alpha unless both US11 and ICP34.5 were absent.

223 Enhanced phosphorylated eIF2alpha correlates with high rates of recrudescence fo

224 ase caused enhanced levels of phosphorylated eIF2alpha and activating transcription factor (ATF) 4, w

225 Low levels of phosphorylated eIF2alpha correlated with continued protein synthesis an

226 UPR signaling at the level of phosphorylated eIF2alpha is neuroprotective and avoids the pancreatic t

227 hat suppresses the effects of phosphorylated eIF2alpha on mRNA translation, was sufficient to reverse

228 thy despite reduced levels of phosphorylated eIF2alpha.

229 s besides the UPR converge on phosphorylated eIF2alpha in the integrated stress response (ISR), which

230 t Thr(980) Subsequently, PERK phosphorylated eIF2alpha at Ser(51), upregulating its downstream effect

231 uitinates, and stabilizes the phosphorylated eIF2alpha (p-eIF2alpha) but not activating transcription

232 CGG and G4C2 repeats trigger phosphorylated-eIF2alpha-dependent stress granule formation and global

233 to nutrient deprivation, Gcn2 phosphorylates eIF2alpha, thereby repressing general translation while

234 and oxidative stress, and it phosphorylates eIF2alpha (eIF2alphaP), which inhibits the translation o

235 lpha kinase GCN2 rhythmically phosphorylates eIF2alpha in the suprachiasmatic circadian clock.

236 HRI) controls translation by phosphorylating eIF2alpha.

237 s pool of activated PKR from phosphorylating eIF2alpha, even following exposure to the synthetic dsRN

238 ce with decreased eIF2alpha phosphorylation (eIF2alpha(+/S51A)) exhibit reduced responses to noxious

239 binding to conserved amino acids in the PKR eIF2alpha binding site and blocking PKR kinase activity.

240 egulated eIF2alpha phosphorylation and a PKR-eIF2alpha pathway in cell apoptosis may be an important

241 inhibits apoptosis of HEK293T cells in a PKR-eIF2alpha-dependent manner, with concurrent up- and down

242 s but this does not apparently result in PKR-eIF2alpha activation that normally induces an anti-viral

243 hosphorylation is mediated by the Plasmodium eIF2alpha kinase, PK4.

244 lls, US11 cooperated with ICP34.5 to prevent eIF2alpha phosphorylation late in infection.

245 he dephosphorylation of eIF2alpha, prolonged eIF2alpha phosphorylation and improved motor, neurophysi

246 We confirmed that Sephin1 prolonged eIF2alpha phosphorylation in stressed primary oligodendr

247 deactivates this pathway whereas prolonging eIF2alpha phosphorylation enhances cell survival.

248 This phosphorylation event reduced eIF2alpha binding to PERK and selectively attenuated dow

249 n both fibroblasts and mice, whereas reduced eIF2alpha phosphorylation lengthens the circadian period

250 We found that learning reduces eIF2alpha phosphorylation in hippocampal excitatory neur

251 Phosphorylation refolds eIF2alpha, allowing it to contact eIF2B at a different i

252 Heme-regulated eIF2alpha kinase (HRI) controls translation by phosphory

253 Heme-regulated eIF2alpha kinase (HRI) is a key hemoprotein in erythroid

254 Heme-regulated eIF2alpha kinase, also known as heme-regulated inhibitor

255 Involvement of PC1-regulated eIF2alpha phosphorylation and a PKR-eIF2alpha pathway in

256 stress-induced ISR, mediated by the related eIF2alpha kinase PERK.

257 As part of this adaptive response, eIF2alpha-P also induces a feedback mechanism through en

258 -globin gene requires the erythroid-specific eIF2alpha kinase heme-regulated inhibitor (HRI), suggest

259 On stress, eIF2alpha-P localizes predominately to larger bodies and

260 poses the binding site for the PKR substrate eIF2alpha.

261 ukaryotic initiation factor 2 alpha subunit (eIF2alpha) signaling and ER stress markers under normal-

262 rrent with reduced global protein synthesis, eIF2alpha-P and the accompanying integrated stress respo

263 We conclude that eIF2alpha-P is cytoprotective in response to UVB by a me

264 Our findings establish that eIF2alpha phosphorylation regulates not only cell-autono

265 this study, we provide genetic evidence that eIF2alpha phosphorylation has a protective role in CMT1B

266 Our results support the hypothesis that eIF2alpha phosphorylation is protective in CMT1B and unv

267 We showed that eIF2alpha phosphorylation did not inhibit protein synthe

268 Collectively, our findings suggest that eIF2alpha-mediated translational control regulates the p

269 The eIF2alpha kinase GCN2 rhythmically phosphorylates eIF2al

270 egulation is a universal hallmark across the eIF2alpha kinase family under various stress conditions

271 here it interacts with HRI and activates the eIF2alpha kinase activity of HRI.

272 Here we show that HRI is the eIF2alpha kinase that is necessary and sufficient for th

273 r C/EBP homologous protein that mediates the eIF2alpha-dependent integrated stress response.

274 contrast, inhibiting the ISR by mutating the eIF2alpha phosphorylation site, genetically(11) and phar

275 a levels required rhythmic activation of the eIF2alpha kinase CPC-3 (the homolog of yeast and mammali

276 to suppress food intake, but the role of the eIF2alpha phosphatases in regulating body weight is poor

277 n C. burnetii and specific components of the eIF2alpha signaling cascade to parasitize human macropha

278 nfection despite continued activation of the eIF2alpha signaling pathway.

279 Phosphorylation of the eIF2alpha subunit in response to various cellular stress

280 We found that the eIF2alpha kinase heme-regulated inhibitor (HRI) controls

281 Recently, we found that the eIF2alpha kinase heme-regulated inhibitory (HRI) induced

282 letes asparagine, activating the ISR via the eIF2alpha kinase GCN2.

283 monstrate that translational control through eIF2alpha phosphorylation is required for normal keratin

284 ite sides of an eIF2B hetero-decamer through eIF2alpha-D1, which contains the phosphorylated Ser51.

285 PKR inhibits translation initiation through eIF2alpha phosphorylation, which triggers stress granule

286 ) show that translational repression through eIF2alpha phosphorylation mediated by PK4 kinase activit

287 Thus, eIF2alpha-dependent mRNA translation controls memory con

288 the highly conserved GCN2 kinase, leading to eIF2alpha phosphorylation and thus affecting the status

289 age promoted cross-talk signaling and led to eIF2alpha phosphorylation.

290 vent stress granule formation in response to eIF2alpha phosphorylation.

291 2,14)-prostaglandin J2 (15-d-PGJ2), triggers eIF2alpha phosphorylation, thereby activating the ISR, r

292 Two eIF2alpha phosphatases, containing GADD34 and CReP, cata

293 sely, uS7-D215 substitutions, perturbing uS7-eIF2alpha interaction in the closed state, confer the op

294 Thus, remodeling of the uS7/eIF2alpha interface appears to stabilize first the open,

295 or the inhibition of eIF2B activity, whereby eIF2alpha phosphorylation destabilizes an autoregulatory

296 athy through the generation of mice in which eIF2alpha cannot be phosphorylated specifically in Schwa

297 fects against misfolding by interfering with eIF2alpha-P dephosphorylation through selective disrupti

298 nes restore proteostasis by interfering with eIF2alpha-P dephosphorylation.

299 tions of eIF2alpha kinases or treatment with eIF2alpha kinase inhibitors being protective in some ani

300 regulatory intramolecular interaction within eIF2alpha; and (ii) the first structural model for the c