Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis

Hao Gu, Chiqi Chen, Xiaoxin Hao, Conghui Wang, Xiaocui Zhang, Zhen Li, Hongfang Shao, Hongxiang Zeng, Zhuo Yu, Li Xie, Fangzhen Xia, Feifei Zhang, Xiaoye Liu, Yaping Zhang, Haishan Jiang, Jun Zhu, Jiangbo Wan, Chun Wang, Wei Weng, Jingjing XieMinfang Tao, Cheng Cheng Zhang, Junling Liu, Guo Qiang Chen, Junke Zheng

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Certain secretory proteins are known to be critical for maintaining the stemness of stem cells through autocrine signaling. However, the processes underlying the biogenesis, maturation, and secretion of these proteins remain largely unknown. Here we demonstrate that many secretory proteins produced by hematopoietic stem cells (HSCs) undergo exosomal maturation and release that is controlled by vacuolar protein sorting protein 33b (VPS33B). Deletion of VPS33B in either mouse or human HSCs resulted in impaired exosome maturation and secretion as well as loss of stemness. Additionally, VPS33B deficiency led to a dramatic delay in leukemogenesis. Exosomes purified from either conditioned medium or human plasma could partially rescue the defects of HSCs and leukemia-initiating cells (LICs). VPS33B co-existed in exosomes with GDI2, VPS16B, FLOT1, and other known exosome markers. Mechanistically, VPS33B interacted with the GDI2/RAB11A/RAB27A pathway to regulate the trafficking of secretory proteins as exosomes. These findings reveal an essential role for VPS33B in exosome pathways in HSCs and LICs. Moreover, they shed light on the understanding of vesicle trafficking in other stem cells and on the development of improved strategies for cancer treatment.

Original languageEnglish (US)
Pages (from-to)4537-4553
Number of pages17
JournalJournal of Clinical Investigation
Volume126
Issue number12
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Gu, H., Chen, C., Hao, X., Wang, C., Zhang, X., Li, Z., Shao, H., Zeng, H., Yu, Z., Xie, L., Xia, F., Zhang, F., Liu, X., Zhang, Y., Jiang, H., Zhu, J., Wan, J., Wang, C., Weng, W., ... Zheng, J. (2016). Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis. Journal of Clinical Investigation, 126(12), 4537-4553. https://doi.org/10.1172/JCI87105