Elevated levels of Ube2g1 in hematopoietic stem cells lead to segmental aging of the hematopoietic system

Aged hematopoietic stem cells (HSC) show diminished capacity of self-renewal, skewed lineage output and compromised proteostasis. Ubiquitin proteasomal systems are critical for maintaining protein homeostasis. We show that the levels of Ube2g1, a E2 ubiquitin-conjugating enzyme likely involved in clonal selection of HSC, was elevated in aged murine and human HSC. We hypothesized that elevated levels of Ube2g1 causally contribute to hematopoietic system aging. Elevated levels of Ube2g1 in young murine HSC resulted in increased myeloid-to-lymphoid ratio and reduced naïve T cells, both known hallmarks of hematopoietic aging. Interestingly, the ubiquitination function of Ube2g1 did not primarily account for the observed phenotypes. Elevated levels of Ube2g1 affected global tyrosine phosphorylation, mediated through a Ube2g1-Shp2 axis, which correlated with impaired T-cell development and reduced HSC function. Our work identifies a novel connection between proteins involved in the regulation of ubiquitination and phosphorylation in HSC that affect phenotypes linked to aging of HSC.