Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNA^Leu(TAA). SLFN12 selectively digests tRNA^Leu(TAA), and velcrin treatment promotes the cleavage of tRNA^Leu(TAA) by inducing PDE3A–SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNA^Leu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNA^Leu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNA^Leu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.

Velcrin 化合物通过诱导这两种蛋白质之间形成复合物来杀死表达高水平磷酸二酯酶 3A (PDE3A) 和 Schlafen 家族成员 12 (SLFN12) 的癌细胞，但 PDE3A-SLFN12 复合物杀死癌细胞的机制尚不完全清楚。在这里，我们报道 SLFN12 RNase 的生理底物是 tRNA ^Leu (TAA)。SLFN12 选择性消化 tRNA ^Leu (TAA)，velcrin 处理通过诱导体外 PDE3A-SLFN12 复合物形成来促进 tRNA ^Leu (TAA)的裂解。^{我们发现 tRNA Leu} (TAA)的可变环和受体茎中的不同序列是底物消化所必需的。Velcrin 处理敏感细胞会导致 tRNA ^Leu (TAA) 下调、核糖体在 Leu-TTA 密码子处暂停以及蛋白质合成的整体抑制。因此，Velcrin 诱导的 SLFN12 对 tRNA ^Leu (TAA) 的裂解以及随之而来的蛋白质合成的整体抑制定义了一种新的细胞凋亡启动机制。