Proteostasis and Myeloid Stem Cell Production

Hematopoietic stem cells (HSCs) regenerate blood cells lost to turnover, injury and disease. Defects in HSC maintenance, such as those that occur during aging, lead to anemia, impaired immunity, and bone marrow failure. Over- or ectopic activation of HSC self-renewal programs leads to hematopoietic neoplasms. Thus, defects in HSC maintenance can lead to diverse malignant and non-malignant hematopoietic disorders. We recently discovered that HSCs have lower rates of protein synthesis than other blood cells. Low protein synthesis is necessary for HSCs, as genetic changes that increase protein synthesis impair HSC function. Importantly, this does not simply reflect HSC quiescence, as dividing HSCs also have lower rates of protein synthesis as compared to dividing restricted progenitors. However, why stem cells depend on low protein synthesis and how increases in protein synthesis impair stem cell function remain largely unknown. Translation is a key cog in both the gene expression and protein homeostasis (proteostasis) networks, and thus influences both the content and the quality of the proteome. We have now determined that low protein synthesis within HSCs is associated with elevated proteome quality in vivo. HSCs contain less ubiquitylated and unfolded proteins as compared to restricted myeloid progenitors, and modest increases in protein synthesis cause an accumulation of misfolded/unfolded proteins within HSCs. Thus, HSCs depend upon low protein synthesis to maintain proteome quality. To test how translational control of proteome quality affects stem cell function, we examined Aars^sti/sti mice that harbor a mutation in the alanyl-tRNA synthetase, which causes a tRNA editing defect that increases amino acid misincorporation errors during translation. Aars^sti/sti mice exhibit reduced HSC numbers and significantly diminished serial reconstituting activity in vivo, but do not exhibit defects within restricted progenitors. Surprisingly, a modest accumulation of misfolded/unfolded proteins does not induce significant activation of the unfolded protein response within HSCs, but instead overwhelms the capacity of the proteasome, which promotes the stabilization and increased abundance of c-Myc. Conditional deletion of a single copy of Myc is sufficient to significantly rescue serial reconstitution defects in Aars^sti/sti HSCs. HSCs are thus dependent on low protein synthesis to maintain proteome quality and homeostasis to preserve their self-renewal activity in vivo.