Hematopoietic stem cells are responsible for generating red blood cells and immune cells. With age, this production of cells becomes dysfunctional in a variety of ways, contributing to the aging of the immune system. For example, production of immune cells becomes biased to myeloid cells at the expense of lymphoid cells, a change that contributes indirectly to the more inflammatory behavior of the aged immune system. Identifying specific mechanisms involved in hemotopoietic aging is the first step on the road to finding ways to reverse these issues.
Aged hematopoietic stem cells (HSCs) 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 HSCs, was elevated in aged murine and human HSCs. We hypothesized that elevated levels of Ube2g1 causally contribute to hematopoietic system aging.
Elevated levels of Ube2g1 in young murine HSCs resulted in increased myeloid-to-lymphoid ratio and reduced naïve T-cells, both known hematopoietic aging hallmarks. Interestingly, the ubiquitination function of Ube2g1 didn't 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 HSCs that affect phenotypes linked to aging of HSCs.
Link: https://doi.org/10.3324/haematol.2025.288847
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