通过 β1 整合素-CD98hc-TRPV4 轴对跨膜机械转导进行分子作图。
Molecular mapping of transmembrane mechanotransduction through the β1 integrin-CD98hc-TRPV4 axis.
机构信息
Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
出版信息
J Cell Sci. 2020 Nov 2;133(20):jcs248823. doi: 10.1242/jcs.248823.
Abstract
One of the most rapid (less than 4 ms) transmembrane cellular mechanotransduction events involves activation of transient receptor potential vanilloid 4 (TRPV4) ion channels by mechanical forces transmitted across cell surface β1 integrin receptors on endothelial cells, and the transmembrane solute carrier family 3 member 2 (herein denoted CD98hc, also known as SLC3A2) protein has been implicated in this response. Here, we show that β1 integrin, CD98hc and TRPV4 all tightly associate and colocalize in focal adhesions where mechanochemical conversion takes place. CD98hc knockdown inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming the mechanospecificity of this signaling response. Molecular analysis reveals that forces applied to β1 integrin must be transmitted from its cytoplasmic C terminus via the CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 in order to produce ultrarapid, force-induced channel activation within the focal adhesion.
摘要
其中一个最快的（小于 4 毫秒）跨膜细胞力学转导事件涉及通过细胞表面 β1 整合素受体在细胞间传递的机械力激活瞬时受体电位香草素 4（TRPV4）离子通道，并且跨膜溶质载体家族 3 成员 2（在此表示为 CD98hc，也称为 SLC3A2）蛋白已被牵连在这种反应中。在这里，我们表明β1 整合素、CD98hc 和 TRPV4 都紧密相关，并在发生力学化学转化的粘着斑中聚集。CD98hc 敲低抑制了机械力诱导的 TRPV4 介导的钙内流，但不抑制化学激活剂诱导的钙内流，从而证实了这种信号转导反应的机械特异性。分子分析表明，必须通过 CD98hc 胞质尾从β1 整合素的胞质 C 端传递施加于β1 整合素的力，才能在粘着斑内产生超快速、力诱导的通道激活。
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