title: Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis.
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.
authors: Hao
authors: H
authors: Gu
authors: Chiqi
authors: C
authors: Chen
authors: Xiaoxin
authors: X
authors: Hao
authors: Conghui
authors: C
authors: Wang
authors: Xiaocui
authors: X
authors: Zhang
authors: Zhen
authors: Z
authors: Li
authors: Hongfang
authors: H
authors: Shao
authors: Hongxiang
authors: H
authors: Zeng
authors: Zhuo
authors: Z
authors: Yu
authors: Li
authors: L
authors: Xie
authors: Fangzhen
authors: F
authors: Xia
authors: Feifei
authors: F
authors: Zhang
authors: Xiaoye
authors: X
authors: Liu
authors: Yaping
authors: Y
authors: Zhang
authors: Haishan
authors: H
authors: Jiang
authors: Jun
authors: J
authors: Zhu
authors: Jiangbo
authors: J
authors: Wan
authors: Chun
authors: C
authors: Wang
authors: Wei
authors: W
authors: Weng
authors: Jingjing
authors: J
authors: Xie
authors: Minfang
authors: M
authors: Tao
authors: Cheng Cheng
authors: CC
authors: Zhang
authors: Junling
authors: J
authors: Liu
authors: Guo-Qiang
authors: GQ
authors: Chen
authors: Junke
authors: J
authors: Zheng
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006410:Hematopoiesis; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport / Q000235:genetics; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins
chemical_list: D020730:Guanine Nucleotide Dissociation Inhibitors; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D000075745:rab27 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C098085:Gdi2 protein, mouse; C000601834:VPS33B protein, mouse; C512962:Rab27a protein, mouse