State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Collaborative Innovation Center of System Biology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Department of Biology, Brandeis University, Waltham, MA, 02454, USA.
Front Med. 2018 Oct;12(5):559-565. doi: 10.1007/s11684-017-0562-3. Epub 2017 Dec 16.
Zfyve16 (a.k.a. endofin or endosome-associated FYVE-domain protein), a member of the FYVE-domain protein family, is involved in endosomal trafficking and in TGF-β, BMP, and EGFR signaling. The FYVE protein SARA regulates the TGF-β signaling pathway by recruiting Smad2/3 and accelerating their phosphorylation, thereby altering their susceptibility to TGF-β-mediated T cell suppression. Zfyve16 binds to Smad4 and their binding affects the formation of Smad2/3-Smad4 complex in TGF-β signaling. However, the in vivo function of Zfyve16 remains unknown. In this study, we generated a Zfyve16 knockout mouse strain (Zfyve16) and examined its hematopoietic phenotypes and hematopoietic reconstruction ability. The proportion of Tcells in the peripheral blood of Zfyve16 mice increases compared with that in wild-type mice. This finding is consistent with the role of Zfyve16 in facilitating TGF-β signaling. Unpredictably, B cell proliferation is inhibited in Zfyve16 mice. The proliferation potential of Zfyve16 B-lymphoid cells also significantly decreases in vitro. These results suggest that Zfyve16 inhibits the proliferation of T cells, possibly through the TGF-β signaling, but upregulates the proliferation of B-lymphoid cells.
Zfyve16（也称为 endofin 或内体相关 FYVE 结构域蛋白）是 FYVE 结构域蛋白家族的一员，参与内体运输以及 TGF-β、BMP 和 EGFR 信号转导。FYVE 蛋白 SARA 通过招募 Smad2/3 并加速其磷酸化来调节 TGF-β 信号通路，从而改变它们对 TGF-β 介导的 T 细胞抑制的敏感性。Zfyve16 与 Smad4 结合，其结合影响 TGF-β 信号转导中 Smad2/3-Smad4 复合物的形成。然而，Zfyve16 的体内功能尚不清楚。在本研究中，我们生成了 Zfyve16 敲除小鼠品系（Zfyve16），并检查了其造血表型和造血重建能力。与野生型小鼠相比，Zfyve16 小鼠外周血中的 T 细胞比例增加。这一发现与 Zfyve16 促进 TGF-β 信号转导的作用一致。出乎意料的是，Zfyve16 小鼠的 B 细胞增殖受到抑制。Zfyve16 B 淋巴细胞的增殖潜力在体外也显著降低。这些结果表明，Zfyve16 通过 TGF-β 信号转导抑制 T 细胞的增殖，但上调 B 淋巴细胞的增殖。
