Phosphatase Shp2 regulates biogenesis of small extracellular vesicles by dephosphorylating Syntenin.
Phosphatase Shp2 regulates biogenesis of small extracellular vesicles by dephosphorylating Syntenin.
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磷酸酶Shp2通过去磷酸化Syntenin调节小细胞外囊泡的生物发生
DOI：
10.1002/jev2.12078
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发表时间：
2021-03
影响因子：
16
通讯作者：
Ke Y
中科院分区：
文献类型：
--
作者：
Zhang Y;Li Y;Liu P;Gong D;Zhou H;Li W;Zhang H;Zheng W;Xu J;Cheng H;Zhang X;Ke Y
细胞外小泡作为细胞间信号转导的新介质，在生理和病理生理过程中发挥着重要作用。到目前为止，支持SEV产生的分子机制还不完全清楚。许多激酶被报道在SEV的产生或组成中起作用，而磷酸酶的参与在很大程度上仍未被探索。在这里，我们揭示了药物抑制和shRNA介导的酪氨酸磷酸酶Shp2的下调显著增加了SEV的形成。通过免疫共沉淀(Co-IP)和体外去磷酸化实验，我们证实Shp2通过直接去磷酸化Syntenin的酪氨酸46来负调控SEV的生物发生，这被报道为SEV生物发生中的一个分子开关。更重要的是，Shp2功能障碍导致体内和体外上皮细胞SEV生成增加。ShRNA介导的Shp2下调导致的上皮性SEV增加，促进巨噬细胞活化，从而加强炎症反应。我们的发现强调了Shp2通过Syntenin Y46的去磷酸化控制SEV的生物发生，从而在调节SEV介导的上皮-巨噬细胞串扰中的作用。本研究确定了细胞间转移的上皮性SEV诱导的肺泡巨噬细胞的增强炎症特征。这些发现为进一步了解SEV的形成机制及其在上皮-巨噬细胞串扰中的作用奠定了基础。
As novel mediators of cell‐to‐cell signalling, small extracellular vesicles (sEVs) play a critical role in physiological and pathophysiological processes. To date, the molecular mechanisms that support sEV generation are incompletely understood. Many kinases are reported for their roles in sEV generation or composition, whereas the involvement of phosphatases remains largely unexplored. Here we reveal that pharmacological inhibition and shRNA‐mediated down‐regulation of tyrosine phosphatase Shp2 significantly increases the formation of sEVs. By Co‐immunoprecipitation (Co‐IP) and in vitro dephosphorylation assays, we identified that Shp2 negatively controlled sEV biogenesis by directly dephosphorylating tyrosine 46 of Syntenin, which has been reported as a molecular switch in sEV biogenesis. More importantly, Shp2 dysfunction led to enhanced epithelial sEV generation in vitro and in vivo. The increase of epithelial sEVs caused by shRNA‐mediated down‐regulation of Shp2 promoted macrophage activation, resulting in strengthened inflammation. Our findings highlight the role of Shp2 in regulating sEV‐mediated epithelial‐macrophage crosstalk by controlling sEV biogenesis through dephosphorylation of Syntenin Y46. The present study determines the strengthened inflammatory characteristics of alveolar macrophages elicited by epithelial sEVs transferred intercellularly. These findings provide a basis for understanding the mechanism of sEV formation and relevant function in epithelial‐macrophage crosstalk.
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影响因子：
16
作者：
Lötvall J;Hill AF;Hochberg F;Buzás EI;Di Vizio D;Gardiner C;Gho YS;Kurochkin IV;Mathivanan S;Quesenberry P;Sahoo S;Tahara H;Wauben MH;Witwer KW;Théry C
通讯作者：
Théry C
DOI：
10.1073/pnas.1521230113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Kowal, Joanna;Arras, Guillaume;Thery, Clotilde
通讯作者：
Thery, Clotilde
DOI：
10.1073/pnas.1713433114
发表时间：
2017-11-21
影响因子：
11.1
作者：
Imjeti NS;Menck K;Egea-Jimenez AL;Lecointre C;Lembo F;Bouguenina H;Badache A;Ghossoub R;David G;Roche S;Zimmermann P
通讯作者：
Zimmermann P
影响因子：
7.3
作者：
Lee H;Abston E;Zhang D;Rai A;Jin Y
通讯作者：
Jin Y
影响因子：
4.4
作者：
Li, Fen-fen;Shen, Jian;Ke, Yuehai
通讯作者：
Ke, Yuehai