PD-L1 去糖基化促进其核转位并加速癌症中的 DNA 双链断裂修复。

PD-L1 deglycosylation promotes its nuclear translocation and accelerates DNA double-strand-break repair in cancer.

机构信息

Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA.

Bioinformatics and Systems Biology Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA, USA.

出版信息

Nat Commun. 2024 Aug 9;15(1):6830. doi: 10.1038/s41467-024-51242-8.

Resistance to radiotherapy is a major barrier during cancer treatment. Here using genome-scale CRISPR/Cas9 screening, we identify CD274 gene, which encodes PD-L1, to confer lung cancer cell resistance to ionizing radiation (IR). Depletion of endogenous PD-L1 delays the repair of IR-induced DNA double-strand breaks (DSBs) and PD-L1 loss downregulates non-homologous end joining (NHEJ) while overexpression of PD-L1 upregulates NHEJ. IR induces translocation of PD-L1 from the membrane into nucleus dependent on deglycosylation of PD-L1 at N219 and CMTM6 and leads to PD-L1 recruitment to DSBs foci. PD-L1 interacts with Ku in the nucleus and enhances Ku binding to DSB DNA. The interaction between the IgC domain of PD-L1 and the core domain of Ku is required for PD-L1 to accelerate NHEJ-mediated DSB repair and produce radioresistance. Thus, PD-L1, in addition to its immune inhibitory activity, acts as mechanistic driver for NHEJ-mediated DSB repair in cancer.

放疗抵抗是癌症治疗中的主要障碍。在这里，我们使用全基因组规模的 CRISPR/Cas9 筛选，鉴定出编码 PD-L1 的 CD274 基因，使肺癌细胞对电离辐射（IR）产生抗性。内源性 PD-L1 的耗竭会延迟 IR 诱导的 DNA 双链断裂（DSBs）的修复，PD-L1 的缺失会下调非同源末端连接（NHEJ），而 PD-L1 的过表达会上调 NHEJ。IR 诱导 PD-L1 从膜易位到核，依赖于 PD-L1 在 N219 和 CMTM6 的去糖基化，导致 PD-L1 募集到 DSB 焦点。PD-L1 在核内与 Ku 相互作用，并增强 Ku 与 DSB DNA 的结合。PD-L1 的 IgC 结构域与 Ku 的核心结构域之间的相互作用对于 PD-L1 加速 NHEJ 介导的 DSB 修复并产生放射抗性是必需的。因此，PD-L1 除了具有免疫抑制活性外，还作为癌症中 NHEJ 介导的 DSB 修复的机制驱动因子。