Modest Declines in Proteome Quality Impair Hematopoietic Stem Cell Self-Renewal

Abstract

Summary: Low protein synthesis is a feature of somatic stem cells that promotes regeneration in multiple tissues. Modest increases in protein synthesis impair stem cell function, but the mechanisms by which this occurs are largely unknown. We determine that low protein synthesis within hematopoietic stem cells (HSCs) is associated with elevated proteome quality in vivo. HSCs contain less misfolded and unfolded proteins than myeloid progenitors. Increases in protein synthesis cause HSCs to accumulate misfolded and unfolded proteins. To test how proteome quality affects HSCs, we examine Aarssti/sti mice that harbor a tRNA editing defect that increases amino acid misincorporation. Aarssti/sti mice exhibit reduced HSC numbers, increased proliferation, and diminished serial reconstituting activity. Misfolded proteins overwhelm the proteasome within Aarssti/sti HSCs, which is associated with increased c-Myc abundance. Deletion of one Myc allele partially rescues serial reconstitution defects in Aarssti/sti HSCs. Thus, HSCs are dependent on low protein synthesis to maintain proteostasis, which promotes their self-renewal. : Stem cells in multiple tissues depend on low protein synthesis to promote regeneration. Hidalgo San Jose et al. demonstrate that low protein synthesis promotes hematopoietic stem cell function by restricting the biogenesis of misfolded proteins. Misfolded proteins impair stem cell quiescence and self-renewal by overwhelming the proteasome and disrupting proteostasis. Keywords: hematopoietic stem cell, HSC, stem cell, proteostasis, protein homeostasis, translation, protein synthesis, protein quality control, self-renewal