Clec16a maintains definitive hematopoietic stem and progenitor cells via mitophagy PMID: 41719124

ADC Targets in Oncology

2026-04-10

Clec16a maintains definitive hematopoietic stem and progenitor cells via mitophagy

Cell Rep. 2026 Mar 24;45(3):116978. doi: 10.1016/j.celrep.2026.116978.

Shuyang Cai ¹ , Qian Zhang ¹ , Qian Luo ² , Honghu Li ³ , Yuchen Tao ¹ , Cong Feng ⁴ , Ruxiu Tie ³ , Xiangjun Zeng ³ , Shuo Chen ⁵ , Zijun Song ⁶ , Anli Wang ⁷ , Qi Hu ¹ , Jizhang Bao ¹ , Yang Su ¹ , Yirong Chen ¹ , Hao Xu ¹ , Kexin Hu ¹ , Ning Ding ¹ , Runfeng Ni ¹ , Rui Jin ¹ , Fan Wu ¹ , Xiaojing Li ¹ , Xinyi Yang ¹ , Yang Xu ⁸ , He Huang ⁹ , Jiahui Lu ¹⁰

Affiliations

1. Clinical Hematology Center and Institute of Hematology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2. Department of Ultrasound in Medicine, the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China; Research Center of Ultrasound in Medicine and Biomedical Engineering, the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
3. Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
4. Department of Bioinformatics, College of Life Sciences, Zhejiang University, Hangzhou, China.
5. Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
6. The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
7. College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China.
8. State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China. Electronic address: [email protected].
9. Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. Electronic address: [email protected].
10. Clinical Hematology Center and Institute of Hematology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: [email protected].

Abstract

Hematopoietic stem and progenitor cells (HSPCs) arise from hemogenic endothelium via the endothelial-to-hematopoietic transition (EHT), a process requiring precise mitochondrial quality control. Here, we identify Clec16a, an E3 ubiquitin Ligase, as a conserved regulator of embryonic HSPC emergence. In zebrafish and HEK293T models, Clec16a is enriched in hemogenic endothelium, and its loss disrupts arterial identity, impairs EHT, and reduces lymphoid, erythroid, and myeloid lineages. Transcriptomic and proteomic analyses show that Clec16a deficiency compromises Mitophagy by promoting aberrant K48-linked ubiquitination and proteasomal degradation of ATG5, leading to mitochondrial dysfunction and elevated Reactive Oxygen Species. These findings establish Clec16a as an essential regulator linking ubiquitin signaling, Mitophagy, and hematopoietic fate specification. Our study defines a mitophagy-dependent checkpoint that safeguards mitochondrial homeostasis during developmental hematopoiesis and provides insight into the metabolic control of hematopoietic disorders.

Keywords

Atg5; CP: metabolism; CP: stem cell research; Clec16a; USP8; hematopoietic stem and progenitor cell; mitophagy; non-degradative ubiquitination; zebrafish.