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Elevated levels of Ube2g1 in HSCs lead to segmental aging of the haematopoietic system

ABSTRACT: Aged hematopoietic stem cells (HSCs) show diminished capacity of self-renewal, skewed lineage output and compromised proteostasis. Ubiquitin proteasomal systems (UPS) 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 the elevated levels of Ube2g1 causally contribute to aging of the hematopoietic system. Elevated levels of Ube2g1 in young HSCs resulted in increased myeloid-to-lymphoid ratio and reduced naive T cell subpopulations, known hallmarks of aging in hematopoiesis. 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 function of HSCs. Our work identifies a novel connection between proteins involved in the regulation of ubiquitination and the level of phosphorylation in HSCs that affect phenotypes linked to aging of HSCs.

INSTRUMENT(S): LTQ Orbitrap Velos Pro

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Hartmut Geiger

PROVIDER: MSV000098473 | MassIVE | Thu Jul 10 07:19:00 BST 2025

REPOSITORIES: MassIVE

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

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