Tetraspanin-6 negatively regulates exosome production
Tetraspanin-6 negatively regulates exosome production
复制标题
四跨膜蛋白-6负调控外泌体的产生
DOI：
10.1073/pnas.1922447117
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发表时间：
2020-03-17
影响因子：
11.1
通讯作者：
Zimmermann, Pascale
中科院分区：
文献类型：
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作者：
Ghossoub, Rania;Chery, Marion;Zimmermann, Pascale
外泌体是起源于内体的细胞外囊泡（EVs），在生理和疾病中作为细胞间信号传导的主要调节因子出现。外显体高度富含四跨蛋白（tspn）和syndecans (sdc)，后者主要以蛋白质水解裂解形式出现，作为蛋白质的跨膜c端片段。虽然这两个蛋白家族都是膜支架，它们在外泌体的形成、组成和活性中发挥着重要作用，但我们目前忽略了它们是否共同作用来控制外泌体的生物学。在这里，我们发现TSPN6，一种特征不明显的四跨蛋白，作为外泌体释放的负调节因子，支持SDC4和syntenin的溶酶体降解。我们证明了TSPN6与SDC4紧密结合，SDC4-TSPN6的结合决定了TSPN6与syntenin的结合，以及TSPN6依赖于SDC4-syntenin的溶酶体降解。TSPN6也抑制SDC4外结构域的脱落，模仿基质金属蛋白酶抑制剂的作用。综上所述，我们的数据确定了TSPN6是SDC4运输和加工的调节因子，并强调了这些膜支架之间产生外泌体的重要物理和功能连接。这些发现澄清了我们对控制EV形成的分子决定因素的理解，并对EV相关的生物医学具有潜在的广泛影响。
Exosomes, extracellular vesicles (EVs) of endosomal origin, emerge as master regulators of cell-to-cell signaling in physiology and disease. Exosomes are highly enriched in tetraspanins (TSPNs) and syndecans (SDCs), the latter occurring mainly in proteolytically cleaved form, as membrane-spanning C-terminal fragments of the proteins. While both protein families are membrane scaffolds appreciated for their role in exosome formation, composition, and activity, we currently ignore whether these work together to control exosome biology. Here we show that TSPN6, a poorly characterized tetraspanin, acts as a negative regulator of exosome release, supporting the lysosomal degradation of SDC4 and syntenin. We demonstrate that TSPN6 tightly associates with SDC4, the SDC4-TSPN6 association dictating the association of TSPN6 with syntenin and the TSPN6-dependent lysosomal degradation of SDC4-syntenin. TSPN6 also inhibits the shedding of the SDC4 ectodomain, mimicking the effects of matrix metalloproteinase inhibitors. Taken together, our data identify TSPN6 as a regulator of the trafficking and processing of SDC4 and highlight an important physical and functional interconnection between these membrane scaffolds for the production of exosomes. These findings clarify our understanding of the molecular determinants governing EV formation and have potentially broad impact for EV-related biomedicine.