title: Stress-inducible phosphoprotein 1 has unique cochaperone activity during development and regulates cellular response to ischemia via the prion protein.
abstract: Stress-inducible phosphoprotein 1 (STI1) is part of the chaperone machinery, but it also functions as an extracellular ligand for the prion protein. However, the physiological relevance of these STI1 activities in vivo is unknown. Here, we show that in the absence of embryonic STI1, several Hsp90 client proteins are decreased by 50%, although Hsp90 levels are unaffected. Mutant STI1 mice showed increased caspase-3 activation and 50% impairment in cellular proliferation. Moreover, placental disruption and lack of cellular viability were linked to embryonic death by E10.5 in STI1-mutant mice. Rescue of embryonic lethality in these mutants, by transgenic expression of the STI1 gene, supported a unique role for STI1 during embryonic development. The response of STI1 haploinsufficient mice to cellular stress seemed compromised, and mutant mice showed increased vulnerability to ischemic insult. At the cellular level, ischemia increased the secretion of STI1 from wild-type astrocytes by 3-fold, whereas STI1 haploinsufficient mice secreted half as much STI1. Interesting, extracellular STI1 prevented ischemia-mediated neuronal death in a prion protein-dependent way. Our study reveals essential roles for intracellular and extracellular STI1 in cellular resilience.
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Flavio H
authors.initials: FH
authors.lastname: Beraldo
authors.forename: Iaci N
authors.initials: IN
authors.lastname: Soares
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Goncalves
authors.forename: Jue
authors.initials: J
authors.lastname: Fan
authors.forename: Anu A
authors.initials: AA
authors.lastname: Thomas
authors.forename: Tiago G
authors.initials: TG
authors.lastname: Santos
authors.forename: Amro H
authors.initials: AH
authors.lastname: Mohammad
authors.forename: Martin
authors.initials: M
authors.lastname: Roffé
authors.forename: Michele D
authors.initials: MD
authors.lastname: Calder
authors.forename: Simona
authors.initials: S
authors.lastname: Nikolova
authors.forename: Glaucia N
authors.initials: GN
authors.lastname: Hajj
authors.forename: Andre L
authors.initials: AL
authors.lastname: Guimaraes
authors.forename: Andre R
authors.initials: AR
authors.lastname: Massensini
authors.forename: Ian
authors.initials: I
authors.lastname: Welch
authors.forename: Dean H
authors.initials: DH
authors.lastname: Betts
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.forename: Maria
authors.initials: M
authors.lastname: Drangova
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Watson
authors.forename: Robert
authors.initials: R
authors.lastname: Bartha
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
authors.forename: Vilma R
authors.initials: VR
authors.lastname: Martins
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D015153:Blotting, Western; D000071616:CDX2 Transcription Factor; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007511:Ischemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D006360:Heat-Shock Proteins; D018398:Homeodomain Proteins; D018832:Molecular Chaperones; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D011328:Prions; C489791:Stip1 protein, mouse; D014157:Transcription Factors
keywords: Hsp70; Hsp90; maternal-effect gene; prion protein; stroke