Protein Phase Separation in Hematopoietic Stem Cell Aging

Imbalanced protein homeostasis (proteostasis) is a driver of aging and a vulnerability for long-lived cells such as hematopoietic stem cells. To determine critical proteostasis factors, we analyzed the proteome of hematopoietic stem and progenitor cells and found prolyl isomerases to be the dominant cytosolic chaperones. Genetic removal of prolyl isomerases led to accelerated aging in the stem cell compartment. We identified intrinsically disordered proteins as common substrates of these chaperones, including several key players that control phase transition. Phase separation allows the formation of supramolecular membrane-less organelles that regulate DNA and RNA biology as well as protein translation. Using microscopy and biochemistry, we show that prolyl isomerases promote phase separation and thereby increase cellular resistance to stress. Our research links a ubiquitously expressed chaperone family to phase transition and identifies macromolecular condensation dynamics as a driver of blood stem cell aging.