Apoptosis is triggered by either extrinsic factors, such as ligands of death receptors, or intrinsic factors, such as cytochrome c, which when released from mitochondria causes oligomerization of Apaf-1 and the assembly of a complex called the apoptosome. Formation of the apoptosome triggers the recruitment and proteolytic cleavage of procaspase 9, which then activates caspase 3, the effector caspase, leading to apoptosis (see van Raam and Salvesen). Noting that adenosine triphosphate (ATP) or deoxyadenosine triphosphate (dATP) is required for apoptosome assembly, Mei et al. found that pretreatment of cytosolic extracts with RNase A, which hydrolyzes RNA to nucleotides, enhanced the cytochrome c–dependent activation of caspases 9 and 3. Conversely, addition of total RNA to cell extracts inhibited cytochrome c–dependent activation of caspases. Total RNA inhibited the oligomerization of Apaf-1, and pull-down assays demonstrated that total RNA blocked the interaction between cytochrome c and Apaf-1. Immunoprecipitation studies showed that, of the different species of RNA, only transfer RNA (tRNA), which plays a major role in protein synthesis, bound to cytochrome c, with mitochondrial tRNAs binding more strongly than did cytosolic tRNAs. Microinjection of cells with cytochrome c and purified tRNAs reduced the extent of apoptosis compared to that in cells injected with cytochrome c alone. The tRNA-specific ribonuclease onconase degraded tRNA in treated cells, which was followed by the activation of caspases 9 and 3. In addition, onconase enhanced the extent of apoptosis induced by the genotoxic drug doxorubicin. Together, these data suggest that tRNAs inhibit cytochrome c–dependent apoptosis and that tRNAs, which are more abundant in transformed cells than in normal cells, may be an effective therapeutic target for tumor therapy.
Y. Mei, J. Yong, H. Liu, Y. Shi, J. Meinkoth, G. Dreyfuss, X. Yang, tRNA binds to cytochrome c and inhibits caspase activation. Mol. Cell 37, 668–678 (2010). [Online Journal]
B. J. van Raam, G. S. Salvesen, Transferring death: A role for tRNA in apoptosis regulation. Mol. Cell 37, 591–592 (2010). [Online Journal]