Mechanism of sphingosine 1-phosphate clearance from blood
Mechanism of sphingosine 1-phosphate clearance from blood
复制标题
DOI：
10.1042/bcj20190730
复制
发表时间：
2020-03-01
影响因子：
4.1
通讯作者：
Lynch, Kevin R.
中科院分区：
文献类型：
--
作者：
Kharel, Yugesh;Huang, Tao;Lynch, Kevin R.
1-磷酸鞘氨醇（S1 P）合成酶和降解酶以及S1 P输出者的相互作用产生了浓度梯度，这是S1 P生物学的基础。细胞外S1 P水平，如血液和淋巴中，相对于细胞S1 P是高的。血液-组织S1 P梯度维持内皮完整性，而局部S1 P梯度影响免疫细胞定位。实际上，当用作多发性硬化症药物的S1 P受体激动剂的作用机制被揭示为抑制T淋巴细胞识别传出淋巴中的高S1 P时，S1 P梯度的重要性最初被认识到。此外，红细胞S1 P的增加，在高原习服过程中缺氧反应影响氧输送。然而，对S1 P梯度如何维持的理解是不完整的。例如，S1 P是合成的，但仅被血液缓慢代谢，而循环中的S1 P通过未知的机制迅速转化。通过反直觉的观察，即血液S1 P响应于抑制S1 P合成（通过鞘氨醇激酶2（SphK 2））而显著增加，我们研究了其中几种组织缺乏SphK 2或S1 P降解酶的小鼠。我们的数据揭示了一种机制，即S1 P在肝细胞表面去磷酸化，所得的鞘氨醇被SphK磷酸化螯合，进而被细胞内S1 P裂解酶降解。因此，我们确定了肝脏作为血液S1 P清除的主要部位，并为SphK 2在此过程中的作用提供了解释。我们的发现表明了S1 P梯度形成的一般机制。
The interplay of sphingosine 1-phosphate (S1P) synthetic and degradative enzymes as well as S1P exporters creates concentration gradients that are a fundamental to S1P biology. Extracellular S1P levels, such as in blood and lymph, are high relative to cellular S1P. The blood-tissue S1P gradient maintains endothelial integrity while local S1P gradients influence immune cell positioning. Indeed, the importance of S1P gradients was recognized initially when the mechanism of action of an S1P receptor agonist used as a medicine for multiple sclerosis was revealed to be inhibition of T-lymphocytes' recognition of the high S1P in efferent lymph. Furthermore, the increase in erythrocyte S1P in response to hypoxia influences oxygen delivery during high altitude acclimatization. However, understanding of how S1P gradients are maintained is incomplete. For example, S1P is synthesized but is only slowly metabolized by blood yet circulating S1P turns over quickly by an unknown mechanism. Prompted by the counterintuitive observation that blood S1P increases markedly in response to inhibition S1P synthesis (by sphingosine kinase 2 (SphK2)), we studied mice wherein several tissues were made deficient in either SphK2 or S1P degrading enzymes. Our data reveal a mechanism whereby S1P is de-phosphorylated at the hepatocyte surface and the resulting sphingosine is sequestered by SphK phosphorylation and in turn degraded by intracellular S1P lyase. Thus, we identify the liver as the primary site of blood S1P clearance and provide an explanation for the role of SphK2 in this process. Our discovery suggests a general mechanism whereby S1P gradients are shaped.