2. Academic Validation
  3. USP7 sustains hematopoietic stem cell homeostasis partially via PU.1 stabilization

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

  • Int J Biol Sci. 2026 Jan 1;22(2):1036-1052. doi: 10.7150/ijbs.123712.
Huizhuang Shan 1 2,  Youping Zhang 1,  Xinhua Xiao 3,  Wenxuan Wu 1,  Yingying Wang 1,  Chujiao Zhu 1,  Wenhui Bai 1,  Ziwei Zhang 4,  Yuanhui Zhai 1,  Li Yang 5,  Yunzhao Wu 4,  Hu Lei 1,  Hanzhang Xu 1,  Yanfei Luo 2,  Liming Lu 6,  Yingli Wu 1 5
Affiliations

Affiliations

  • 1 Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 2 Department of Clinical Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, Guangdong, China.
  • 3 Department of Hematology and Oncology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510000, Guangdong, China.
  • 4 Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
  • 5 Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 6 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
PMID: 41522346 DOI: 10.7150/ijbs.123712
Abstract

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.

Keywords

PU.1; USP7; hematopoiesis; hematopoietic stem cell.

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