USP7 sustains hematopoietic stem cell homeostasis partially via PU.1 stabilization

作者：Huizhuang Shan, Youping Zhang, Xinhua Xiao, Wenxuan Wu, Yingying Wang, Chujiao Zhu, Wenhui Bai, Ziwei Zhang, Yuanhui Zhai, Li Yang, Yunzhao Wu, Hu Lei, Hanzhang Xu, Yanfei Luo, Liming Lu, Yingli Wu · 发表于：International Journal of Biological Sciences · 年份：2026 · DOI：10.7150/ijbs.123712 · 被引用次数：1 · 研究领域：Ubiquitin and proteasome pathways、Acute Myeloid Leukemia Research、Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell (HSC) self-renewal and lineage commitment are tightly controlled by post-translational mechanisms, but the contribution of deubiquitination to these processes remains unclear.Here, we define ubiquitin-specific protease 7 (USP7) as a critical regulator of HSC maintenance and hematopoietic homeostasis.Conditional Usp7 deletion in murine HSCs triggered rapid stem cell depletion, multilineage cytopenias, and systemic hematopoietic failure.Usp7-deficient HSCs displayed defective quiescence, reduced competitive repopulation capacity, and aberrant lineage differentiation.Mechanistically, USP7 directly binds and deubiquitinates the transcription factor PU.1, shielding it from proteasomal degradation.Loss of USP7 destabilized PU.1, leading to suppressed expression of PU.1 target genes critical for HSC quiescence and lineage specification.In competitive transplants, USP7-null HSCs exhibited severely impaired self-renewal, marked by diminished engraftment and differentiation.Ectopic PU.1 expression partially restored HSC function, confirming the USP7-PU.1 axis as essential for HSC integrity.Our study identifies USP7 as a post-translational checkpoint in hematopoiesis and reveals a novel deubiquitination-dependent mechanism controlling stem cell fate.These findings highlight the USP7-PU.1 interaction as a potential therapeutic target for hematopoietic disorders.