Erythropoietin-directed erythropoiesis depends on serpin inhibition of erythroblast lysosomal cathepsins

Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for red blood cell production and exert important cytoprotective effects on select vascular, immune, and cancer cells. To discover novel EPO action modes, we profiled the transcriptome of primary erythroid progenitors. We report...

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Bibliographic Details
Published inThe Journal of experimental medicine Vol. 210; no. 2; pp. 225 - 232
Main Authors Dev, Arvind, Byrne, Susan M, Verma, Rakesh, Ashton-Rickardt, Philip G, Wojchowski, Don M
Format Journal Article
LanguageEnglish
Published United States The Rockefeller University Press 11.02.2013
Subjects
Anemia - genetics
Anemia - metabolism
Animals
Brief Definitive Report
Cathepsin B - antagonists & inhibitors
Cathepsin B - deficiency
Cathepsin B - genetics
Cathepsin L - antagonists & inhibitors
Cathepsins - antagonists & inhibitors
Erythroblasts - cytology
Erythroblasts - metabolism
Erythropoiesis - drug effects
Erythropoiesis - physiology
Erythropoietin - physiology
Lysosomes - metabolism
Mice
Mice, Knockout
Receptors, Erythropoietin - physiology
Serpins - deficiency
Serpins - genetics
Serpins - physiology
Signal Transduction
Transcriptome
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Summary:Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for red blood cell production and exert important cytoprotective effects on select vascular, immune, and cancer cells. To discover novel EPO action modes, we profiled the transcriptome of primary erythroid progenitors. We report Serpina3g/Spi2A as a major new EPO/EPOR target for the survival of erythroid progenitors. In knockout mice, loss of Spi2A worsened anemia caused by hemolysis, radiation, or transplantation. EPO-induced erythropoiesis also was compromised. In particular, maturing erythroblasts required Spi2A for cytoprotection, with iron and reactive oxygen species as cytotoxic agents. Spi2A defects were ameliorated by cathepsin-B/L inhibition, and by genetic co-deletion of lysosomal cathepsin B. Pharmacological inhibition of cathepsin B/L enhanced EPO-induced red cell formation in normal mice. Overall, we define an unexpected EPO action mode via an EPOR-Spi2A serpin-cathepsin axis in maturing erythroblasts, with lysosomal cathepsins as novel therapeutic targets.
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A. Dev and S.M. Byrne contributed equally to this paper.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20121762