EGFR mimotope alleviates renal fibrosis by promoting EGFR/RPL6/PCBP2 ternary complex formation

Epidermal growth factor receptor (EGFR) signalling plays a crucial role in renal fibrosis. We previously demonstrated that EGFR mimotope vaccination could alleviate renal fibrosis by restoring major histocompatibility complex class IB (MHC-IB) expression in renal tubular epithelial cells and promoting MHC-IB-enriched exosome release. Intriguingly, the mechanism by which the EGFR mimotope affects MHC-IB remains unknown. In this study, we demonstrated that administering purified EGFR mimotope-induced antibodies (EM-pAb) can effectively upregulate ribosomal protein ligand (RPL)-6, poly (rC) binding protein 2 (PCBP2), and MHC-IB in tubular epithelial cells. Mechanistically, the EM-pAb promoted EGFR/ribosomal protein ligand 6 (RPL6)/poly (rC) binding protein 2 (PCBP2) functional ternary complex formation, re-established the binding capability of PCBP2 to MHC-IB β-chain, and further regulated the NK cell population. RPL6 was confirmed as the key orchestrator of the ternary complex formation. Rpl6^CKI mice further revealed the protective role of RPL6 in the animal model of renal fibrosis. RPL6 and kidney function showed a significant correlation in patients with chronic kidney disease. Overall, our findings uncover the signalling pathway by which EGFR modulates MHC-IB and validate the regulatory role of EM-pAb in this signalling pathway, indicating the therapeutic potential of RPL6 in chronic kidney disease.