USP18 promotes nasopharyngeal carcinoma radioresistance via TRIM29 oligomerization and ubiquitination

Abstract Radiotherapy, which induces DNA damage to control the progression of local tumors, is the mainstay therapy for nasopharyngeal carcinoma (NPC). However, almost a fifth of patients undergo recurrence. Evidence suggests that ubiquitination is crucial in DNA damage repair (DDR) signaling. In this study, we reveal that the ubiquitin specific peptidase 18 (USP18) is significantly overexpressed in resistant NPC tissues and correlates inversely with NPC cell radiosensitivity. Our findings indicate that USP18 interacts with tripartite motif containing 29 (TRIM29), facilitating its K27-linked ubiquitination independent of USP18’s catalytic activity. USP18 functions as a scaffold, recruiting the E3 ubiquitin ligase tripartite motif containing 21 (TRIM21), which directly ubiquitinates TRIM29 at Lys561. This process promotes TRIM29 oligomerization and nuclear translocation, which enhances DDR in NPC cells after radiotherapy. Clinically, high USP18 levels are associated with worse patient prognosis. Our findings underscore the critical role of USP18 in modulating DDR signaling and radiosensitivity in NPC, suggesting that targeting the USP18-TRIM21-TRIM29 axis may represent a novel strategy to enhance the efficacy of radiotherapy for patients with NPC.