Department of Cardiology, Howard Hughes Medical Institute, Manton Center for Orphan Disease, Children's Hospital Boston, and Department of Neurobiology, Harvard Medical School, Enders Building 1309, 320 Longwood Avenue, Boston, MA 02115, USA.
Dev Cell. 2012 Jun 12;22(6):1149-62. doi: 10.1016/j.devcel.2012.04.006.
Transient receptor potential melastatin-like 7 (TRPM7) is a channel protein that also contains a regulatory serine-threonine kinase domain. Here, we find that Trpm7-/- T cells are deficient in Fas-receptor-induced apoptosis and that TRPM7 channel activity participates in the apoptotic process and is regulated by caspase-dependent cleavage. This function of TRPM7 is dependent on its function as a channel, but not as a kinase. TRPM7 is cleaved by caspases at D1510, disassociating the carboxy-terminal kinase domain from the pore without disrupting the phosphotransferase activity of the released kinase but substantially increasing TRPM7 ion channel activity. Furthermore, we show that TRPM7 regulates endocytic compartmentalization of the Fas receptor after receptor stimulation, an important process for apoptotic signaling through Fas receptors. These findings raise the possibility that other members of the TRP channel superfamily are also regulated by caspase-mediated cleavage, with wide-ranging implications for cell death and differentiation.
瞬时受体电位 melastatin 样 7 型（TRPM7）是一种通道蛋白，也包含一个调节丝氨酸-苏氨酸激酶结构域。在这里，我们发现 Trpm7-/- T 细胞缺乏 Fas 受体诱导的细胞凋亡，并且 TRPM7 通道活性参与凋亡过程，并受 caspase 依赖性切割调节。TRPM7 的这种功能依赖于其作为通道的功能，但不依赖于其作为激酶的功能。TRPM7 在 D1510 处被 caspase 切割，将羧基末端激酶结构域与孔分离，而不会破坏释放的激酶的磷酸转移酶活性，但会显著增加 TRPM7 离子通道活性。此外，我们还表明，TRPM7 在受体刺激后调节 Fas 受体的内吞隔室化，这是 Fas 受体通过凋亡信号转导的一个重要过程。这些发现提出了这样一种可能性，即其他 TRP 通道超家族成员也受到 caspase 介导的切割调节，这对细胞死亡和分化具有广泛的影响。
