Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer

The quaking viable mice have myelination defects and develop a characterist ic tremor 10 d after birth. The quaking gene encodes at least five alternat ively spliced QUAKING (QKI) isoforms that differ in their C-terminal 8-30-a mino-acid sequence. The reason for the existence of the different QKI isofo rms and their function are unknown. Here we show that only one QKI isoform, QKI-7, can induce apoptosis in fibroblasts and primary rat oligodendrocyte s. Heterodimerization of the QKI isoforms results in the nuclear translocat ion of QKI-7 and the suppression of apoptosis. The unique C-terminal 14 ami no acids of QKI-7 confers the ability to induce apoptosis to heterologous p roteins such as the green fluorescent protein and a QKI-related protein, Ca enorhabditis elegans GLD-1. Thus, the unique C-terminal sequences of QKI-7 may function as a life-or-death 'sensor' that monitors the balance between the alternatively spliced QKI isoforms. Moreover, our findings suggest that nuclear translocation is a novel mechanism of inactivating apoptotic induc ers.