The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-11, Vol.118 (47), p.1-7
• Main Authors: De, Sarmishtha, Holvey-Bates, Elise G., Mahen, Kala, Willard, Belinda, Stark, George R.
• Format: Article
• Language: English
• Subjects: A549 Cells; Apoptosis; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Biological Sciences; Cancer; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cisplatin; Cyclin-Dependent Kinase 5; Cyclin-dependent kinases; Damage; Deoxyribonucleic acid; DNA; DNA Damage; F-Box Proteins - genetics; F-Box Proteins - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Immune checkpoint inhibitors; Ionizing radiation; Kinases; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medulloblastoma; Non-small cell lung carcinoma; PD-L1 protein; Phosphorylation; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Sensitivity; Substrate inhibition; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ubiquitins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2112674118

High expression of programmed death-ligand 1 (PD-L1) in cancer cells drives immune-independent, cell-intrinsic functions, leading to resistance to DNA-damaging therapies. We find that high expression of the ubiquitin E3 ligase FBXO22 sensitizes nonsmall cell lung cancer (NSCLC) cells to ionizing radiation (IR) and cisplatin, and that activation of FBXO22 by phosphorylation is necessary for this function. Importantly, FBXO22 activates PD-L1 ubiquitination and degradation, which in turn increases the sensitivity of NSCLC cells to DNA damage. Cyclin-dependent kinase 5 (CDK5), aberrantly active in cancer cells, plays a crucial role in increasing the expression of PD-L1 in medulloblastoma [R. D. Dorand et al., Science 353, 399–403 (2016)]. We show in NSCLC cells that inhibiting CDK5 or reducing its expression increases the level of FBXO22, decreases that of PD-L1, and increases the sensitivity of the cells to DNA damage. We conclude that FBXO22 is a substrate of CDK5, and that inhibiting CDK5 reduces PD-L1 indirectly by increasing FBXO22. Pairing inhibitors of CDK5 with immune checkpoint inhibitors may increase the efficacy of immune checkpoint blockade alone or in combination with DNA-damaging therapies.