Interferon-inducible guanylate-binding proteins (GBPs) are well-known for mediating host-defense mechanisms against cellular pathogens. Emerging evidence suggests that GBPs are also implicated in tumorigenesis; however, their underlying molecular mechanism is still unknown. In this study, we identified that GBP1 and GBP2 interact with MCL-1, the key prosurvival member of the BCL-2 family, via its BH3 domain. GBPs induce caspase-dependent apoptosis in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cells, where the proapoptotic BCL-2 member, BAK, is an indispensable mediator. In particular, GBP2 completely inhibited the MCL-1-mediated promotion of the survival of CML cells through competitive inhibition, resulting in BAK liberation from MCL-1. Concurrently, GBP2 dramatically upregulates BAK expression via its inhibition of the PI3K/AKT pathway. Moreover, paclitaxel upregulates GBP2 expression, and paclitaxel-induced apoptotic activity was distinctively compromised by knockout of GBP2 in CML cells. Bioinformatics analyses of leukemia databases revealed that transcripts of GBPs were generally downregulated in leukemia patients and that GBPs were favorable prognosis markers. Thus, these findings provide molecular evidence of GBPs as apoptosis-inducing proteins of leukemia cells and suggest that GBPs are attractive targets for the development of chemotherapeutics.

干扰素诱导型鸟苷酸结合蛋白 (GBP) 以介导针对细胞病原体的宿主防御机制而闻名。新出现的证据表明 GBP 也与肿瘤发生有关。然而，它们的潜在分子机制仍然未知。在这项研究中，我们确定 GBP1 和 GBP2 通过其 BH3 域与 MCL-1（BCL-2 家族的关键促生存成员）相互作用。GBP 在慢性髓性白血病 (CML) 和急性髓性白血病 (AML) 细胞中诱导半胱天冬酶依赖性细胞凋亡，其中促凋亡 BCL-2 成员 BAK 是不可或缺的介质。特别是GBP2通过竞争性抑制完全抑制了MCL-1介导的CML细胞存活促进，导致BAK从MCL-1中释放出来。同时，GBP2 通过抑制 PI3K/AKT 通路显着上调 BAK 表达。此外，紫杉醇上调 GBP2 表达，紫杉醇诱导的凋亡活性明显受到敲除CML 细胞中的GBP2。白血病数据库的生物信息学分析表明，GBPs 的转录在白血病患者中普遍下调，并且 GBPs 是有利的预后标志物。因此，这些发现提供了 GBP 作为白血病细胞凋亡诱导蛋白的分子证据，并表明 GBP 是开发化疗药物的有吸引力的靶点。