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

Zhen Shu, Bhakti Dwivedi, Jeffrey M. Switchenko, David S. Yu and Xingming Deng ()
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Zhen Shu: Emory University School of Medicine and Winship Cancer Institute of Emory University
Bhakti Dwivedi: Emory University
Jeffrey M. Switchenko: Emory University
David S. Yu: Emory University School of Medicine and Winship Cancer Institute of Emory University
Xingming Deng: Emory University School of Medicine and Winship Cancer Institute of Emory University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51242-8

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