Cleavage of TRPM7 Releases the Kinase Domain from the Ion Channel and Regulates Its Participation in Fas-Induced Apoptosis

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. [Display omitted] ► Deletion of TRPM7 in T cells reduces apoptosis in response to Fas stimulation ► TRPM7 is cleaved by caspases at D1510, dissociating the channel from the kinase ► The TRPM7 channel, but not the released kinase, participates in apoptotic signaling ► TRPM7 regulates Fas receptor internalization TRPM7 is an ion channel that also contains a kinase domain. Desai et al. show that TRPM7 channel activity is regulated by caspase-dependent cleavage, which dissociates the pore from the kinase domain, increasing channel activity. TRPM7 promotes apoptosis by regulating internalization of the Fas receptor.