ISG20L2 通过削弱硼替佐米与 PSMB5 的结合来抑制硼替佐米的抗骨髓瘤活性。
ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5.
机构信息
Department of Hematology, Institute of Hematology, West China Hospital/State Key Laboratory of Biotherapy and Cancer Center and.
State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China.
出版信息
JCI Insight. 2022 Oct 10;7(19):e157081. doi: 10.1172/jci.insight.157081.
The proteasome inhibitors (PIs) bortezomib and carfilzomib, which target proteasome 20S subunit beta 5 (PSMB5) in cells, are widely used in multiple myeloma (MM) treatment. In this study, we demonstrated the role of interferon-stimulated 20 kDa exonuclease-like 2 (ISG20L2) in MM PI resistance. Gain- and loss-of-function studies showed that ISG20L2 suppressed MM cell sensitivity to PIs in vitro and in vivo. Patients with ISG20L2lo MM had a better response to PIs and a longer overall survival than patients with ISG20L2hi MM. Biotinylated bortezomib pull-down assays showed that ISG20L2 competed with PSMB5 in binding to bortezomib. The surface plasmon resonance assay confirmed the direct binding of bortezomib to ISG20L2. In ISG20L2hi MM cells, ISG20L2 attenuated the binding of bortezomib to PSMB5, resulting in lower inhibition of proteasome activity and therefore less bortezomib-induced cell death. Overall, we identified a potentially novel mechanism by which ISG20L2 conferred bortezomib resistance on MM. The expression of ISG20L2 correlated with MM PI responses and patient treatment outcomes.
蛋白酶体抑制剂（PI）硼替佐米和卡非佐米，靶向细胞内蛋白酶体 20S 亚基β5（PSMB5），广泛用于多发性骨髓瘤（MM）的治疗。在这项研究中，我们证实了干扰素刺激的 20kDa 外切酶样 2（ISG20L2）在 MM PI 耐药中的作用。功能获得和缺失研究表明，ISG20L2 抑制 MM 细胞对 PI 的体外和体内敏感性。ISG20L2lo MM 患者对 PI 的反应更好，总生存期更长，而 ISG20L2hi MM 患者则相反。生物素化硼替佐米下拉实验表明，ISG20L2 与 PSMB5 竞争结合硼替佐米。表面等离子体共振分析证实了硼替佐米与 ISG20L2 的直接结合。在 ISG20L2hi MM 细胞中，ISG20L2 减弱了硼替佐米与 PSMB5 的结合，导致蛋白酶体活性的抑制降低，从而减少硼替佐米诱导的细胞死亡。总的来说，我们确定了一种潜在的新机制，即 ISG20L2 赋予 MM 对硼替佐米的耐药性。ISG20L2 的表达与 MM PI 反应和患者治疗结果相关。
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