A common CORIN variant in hypertension reduces corin intracellular trafficking by exposing an inhibitory N-terminus
A common CORIN variant in hypertension reduces corin intracellular trafficking by exposing an inhibitory N-terminus
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高血压中常见的 CORIN 变异通过暴露抑制性 N 末端来减少 Corin 细胞内运输
DOI：
10.1016/j.bbrc.2020.07.023
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发表时间：
2020
影响因子：
3.1
通讯作者：
Wu Qingyu
中科院分区：
文献类型：
--
作者：
He Meiling;Zhang Yue;Li Hui;Liu Meng;Dong Ningzheng;Wu Qingyu
Corin是一种跨膜丝氨酸蛋白酶，可激活心房利钠肽，这是一种对正常血压至关重要的心脏激素。Corin作为酶原合成并在细胞表面活化。在以前的研究中，我们在中国人群中发现了约5%的高血压患者存在编码区5′端腺嘌呤插入的CORIN变异等位基因。这种由CORIN变体等位基因编码的蛋白质名为insA，具有缩短的胞质尾区和降低的心房利钠肽加工活性。目前尚不清楚缩短的胞质尾如何损害corin功能。在这项研究中，我们表达了一系列的corin突变体与不同的N-末端序列，并分析了他们的Western印迹，流式细胞术，蛋白质追逐，和免疫染色。我们的研究结果表明，Gly-Asn序列后，在新产生的N-末端的起始Met负责延迟corin在高尔基体的运输。N-末端Gly和Asn残基的缺失增加了insA变体的细胞内运输、细胞表面表达和活化裂解。这些结果有助于解释corin变异等位基因如何损害corin结构和功能作为高血压的潜在机制。
Corin is a transmembrane serine protease that activates atrial natriuretic peptide, a cardiac hormone essential for normal blood pressure. Corin is synthesized as a zymogen and activated on the cell surface. In previous studies, we identified aCORINvariant allele with an adenine insertion in the 5′-end of the coding region in ∼5% of hypertensive individuals in a Chinese population. The protein, named insA, encoded by theCORINvariant allele has a shortened cytoplasmic tail and reduced atrial natriuretic peptide processing activity. It remains unknown how a shortened cytoplasmic tail impairs corin function. In this study, we expressed a series of corin mutants with different N-terminal sequences and analyzed them by Western blotting, flow cytometry, protein chase, and immunostaining. Our results revealed that a Gly-Asn sequence after the initiating Met at the newly generated N-terminus was responsible for delaying corin trafficking in the Golgi. Deletion of the N-terminal Gly and Asn residues increased the intracellular trafficking, cell surface expression, and activation cleavage of the insA variant. These results help to explain how theCORINvariant allele impairs corin structure and function as an underlying mechanism in hypertension.