1023 – UNIQUE CONFIGURATION OF THE PROTEOSTASIS NETWORK BALANCES HEMATOPOIETIC STEM CELL FITNESS AND LONGEVITY

Abstract

Hematopoietic stem cells (HSCs) persist throughout life to regenerate blood cells lost to physiological turnover, injury and disease. But how stem cells preserve their immense regenerative potential while simultaneously sustaining their remarkable longevity remains a mystery. The regulation of protein homeostasis (proteostasis) has emerged as being fundamentally and preferentially important for HSCs. Proteostasis is maintained by an integrated network of physiological mechanisms and stress response pathways that coordinate protein synthesis, folding, trafficking and degradation to regulate the content and quality of the proteome. Many of these highly-conserved pathways have long been thought of as housekeeping functions, performed similarly by most cells. However, we found that HSCs exhibit unique cell-type-specific configuration of the proteostasis network that is critical for preserving their fitness, health and longevity. Young adult HSCs exhibit unusually low protein synthesis rates to restrict the biogenesis of misfolded proteins in vivo and utilize non-canonical protein trafficking and degradation pathways to limit the accumulation of protein aggregation to preserve their long-term self-renewal potential. Challenges to proteostasis during aging cause HSCs to remodel their proteostasis network to sustain their fitness and regenerative potential. However, adapting to these selective pressures comes at the cost of increasing the risk of premalignant and malignant disease. Overall, unique and dynamic regulation of proteostasis is key for balancing stem cell regeneration and longevity.