UC San Diego

Hematopoietic stem cells (HSCs) are multipotent stem cells that give rise to all blood lineages and persist throughout life to constantly replenish blood cells. To preserve their health and longevity, HSCs are particularly dependent on maintaining protein homeostasis (proteostasis). The proteostasis network oversees protein quality and quantity within a cell, and can be divided into nodes that coordinately oversee protein synthesis, folding, and degradation, as well as respond to proteotoxic stress. HSCs maintain proteostasis partly by sustaining low protein synthesis rates that limit the biogenesis of misfolded proteins. Nevertheless, HSCs ultimately accumulate misfolded proteins that must be eliminated to preserve stem cell fitness. This work aims to address two open questions in the field: what mechanisms HSCs employ to attenuate translation and how HSCs purge misfolded proteins. Here, I investigate the hypothesis that a tRNA code may exist to tune protein synthesis and self-renewal of stem cells. Furthermore, I show that HSCs depend on aggrephagy, a selective form of autophagy, to clear misfolded proteins and maintain proteostasis in vivo. Overall, these studies demonstrate that the proteostasis network is uniquely configured in HSCs to preserve proteostasis and fitness.