期刊
FASEB JOURNAL
卷 27, 期 9, 页码 3594-3607出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.13-232280
关键词
Hsp90; stroke; maternal-effect gene; Hsp70; prion protein
资金
- Canadian Institute of Health Research [MOP 93651, MOP 126000]
- PrioNet-Canada
- Canadian Foundation for Innovation
- Ontario Research Fund
- Alzheimer's Association
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq
- Brazil)
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP
- Sao Paulo, Brazil)
- Department of Foreign Affairs and International Trade (Canada)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Brazil)
- Ontario Graduate Scholarship Program
- FAPESP
- CNPq
- Heart and Stroke Foundation of Canada
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.Beraldo, F. H., Soares, I. N., Goncalves, D. F., Fan, J., Thomas, A. A., Santos, T. G., Mohammad, A. H., Roffe, M., Calder, M. D., Nikolova, S., Hajj, G. N., Guimaraes, A. N., Massensini, A. R., Welch, I., Betts, D. H., Gros, R., Drangova, M., Watson, A. J., Bartha, R., Prado, V. F., Martins, V. R., and Prado, M. A. M. Stress-inducible phosphoprotein 1 has unique cochaperone activity during development and regulates cellular response to ischemia via the prion protein.
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