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PD-L1 (B7-H1) Competes with the RNA Exosome to Regulate the DNA Damage Response and Can Be Targeted to Sensitize to Radiation or Chemotherapy

Tu, Xinyi, Qin, Bo, Zhang, Yong, Zhang, Cheng, Kahila, Mohamed, Nowsheen, Somaira, Yin, Ping, Yuan, Jian, Pei, Huadong, Li, Hu, Yu, Jia, Song, Zhiwang, Zhou, Qin, Zhao, Fei, Liu, Jiaqi, Zhang, Chao, Dong, Haidong, Mutter, Robert W., Lou, Zhenkun
Molecular cell 2019 v.74 no.6 pp. 1215-1226.e4
DNA, DNA damage, RNA-binding proteins, antibodies, drug therapy, exosomes, genes, immune response, ligands, messenger RNA, neoplasms, precipitin tests, programmed cell death, radiotherapy, sequence analysis, tumor suppressor proteins
Programmed death ligand 1 (PD-L1, also called B7-H1) is an immune checkpoint protein that inhibits immune function through its binding of the programmed cell death protein 1 (PD-1) receptor. Clinically approved antibodies block extracellular PD-1 and PD-L1 binding, yet the role of intracellular PD-L1 in cancer remains poorly understood. Here, we discovered that intracellular PD-L1 acts as an RNA binding protein that regulates the mRNA stability of NBS1, BRCA1, and other DNA damage-related genes. Through competition with the RNA exosome, intracellular PD-L1 protects targeted RNAs from degradation, thereby increasing cellular resistance to DNA damage. RNA immunoprecipitation and RNA-seq experiments demonstrated that PD-L1 regulates RNA stability genome-wide. Furthermore, we developed a PD-L1 antibody, H1A, which abrogates the interaction of PD-L1 with CMTM6, thereby promoting PD-L1 degradation. Intracellular PD-L1 may be a potential therapeutic target to enhance the efficacy of radiotherapy and chemotherapy in cancer through the inhibition of DNA damage response and repair.