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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

Author:
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
Source:
Molecular cell 2019 v.74 no.6 pp. 1215-1226.e4
ISSN:
1097-2765
Subject:
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
Abstract:
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.
Agid:
6475795