A degron system targeting endogenous PD-1 inhibits the growth of tumor cells in mice.
A degron system targeting endogenous PD-1 inhibits the growth of tumor cells in mice.
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最近，利用泛素-蛋白酶体系统开发了靶向蛋白质降解系统。在这里，我们建立了程序性细胞死亡-1(PD-1)基因敲除小鼠作为模型系统，使内源性小鼠蛋白受到小分子辅助关闭(SMASH)降解系统的影响。用NS3/4A蛋白水解酶抑制剂asunapvir(ASV)或Grazopvir(GRV)降解Jurkat细胞和CD3+脾细胞上sMash变性标记的PD-1-mCherry。ASV和GRV对接种于Pdcd1-mCherry-sMash纯合子敲除(Ki)小鼠的MC-38结肠腺癌细胞的生长均有抑制作用。此外，GRV治疗后移植KI骨髓细胞的野生型小鼠MC-38细胞的生长受到抑制。这是第一次在体内使用针对内源性小鼠蛋白的降解子标签的研究。我们的实验系统使用sash degron可以用于治疗疾病和表征必需蛋白质的细胞功能。我们将sash degron应用于癌症免疫治疗模型，以减少癌细胞的生长。该系统可用于表征蛋白质的细胞功能和治疗疾病。
Recently, targeted protein degradation systems have been developed using the ubiquitin-proteasome system. Here, we established Programmed cell death-1 (PD-1) knockdown mice as a model system for subjecting endogenous mouse proteins to the small molecule-assisted shutoff (SMASh) degron system. SMASh degron-tagged PD-1-mCherry in Jurkat cells and CD3+ splenocytes were degraded by the NS3/4A protease inhibitors, asunaprevir (ASV) or grazoprevir (GRV). Growth of MC-38 colon adenocarcinoma cells injected in Pdcd1-mCherry-SMASh homozygous knock-in (KI) mice was repressed by ASV or GRV. Moreover, growth of MC-38 cells was suppressed in wild-type mice transplanted with KI bone marrow cells after GRV treatment. This is the first study to use a degron tag targeting an endogenous mouse protein in vivo. Our experimental system using the SMASh degron may be employed for treating diseases and characterizing the cellular functions of essential proteins. We applied the SMASh degron to a cancer immunotherapy model to reduce cancerous growth. This system may be employed for characterizing the cellular functions of proteins and treating diseases.