Differential expression of NEDD8 in different pathological types of chronic rhinosinusitis with nasal polyps / 临床耳鼻咽喉头颈外科杂志

Objective:To analyze the differential expression of neural precursor cell-expressed developmentally downregulated 8（NEDD8） protein in nasal polyp tissues of patients with different pathological types of chronic rhinorhinosinusitis with nasal polyps（CRSwNP）. Methods:All specimens were obtained from the specimen library of Beijing Tongren Hospital, and were all patients who underwent nasal endoscopic surgery for chronic rhinosinusitis in Beijing Tongren Hospital. Hematoxylin-eosin staining（HE） was used to detect the number of eosinophils in nasal polyps, and CRSwNP patients were grouped according to the number of eosinophils in nasal polyps, immunohistochemistry was used to detect and analyze the expression level of NEDD8 protein in nasal polyps. Results:The expression level of NEDD8 protein in nasal polyps of patients with eosinophilic chronic rhinorhinosinusitis with nasal polyps was significantly higher than that of patients with non-eosinophilic chronic rhinosinusitis and nasal polyps（P<0.05）. In addition, there was a significant positive correlation between the expression level of NEDD8 protein and the number of eosinophils in nasal polyp tissue（r=0.79, P=0.02）. Conclusion:There are differences in the expression of NEDD8 protein in patients with chronic rhinosinusitis and nasal polyps of different pathological types.

NEDDylation antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase η in response to oxidative DNA damage

NEDDylation has been shown to participate in the DNA damage pathway, but the substrates of neural precursor cell expressed developmentally downregulated 8 (NEDD8) and the roles of NEDDylation involved in the DNA damage response (DDR) are largely unknown. Translesion synthesis (TLS) is a damage-tolerance mechanism, in which RAD18/RAD6-mediated monoubiquitinated proliferating cell nuclear antigen (PCNA) promotes recruitment of polymerase η (polη) to bypass lesions. Here we identify PCNA as a substrate of NEDD8, and show that E3 ligase RAD18-catalyzed PCNA NEDDylation antagonizes its ubiquitination. In addition, NEDP1 acts as the deNEDDylase of PCNA, and NEDP1 deletion enhances PCNA NEDDylation but reduces its ubiquitination. In response to HO stimulation, NEDP1 disassociates from PCNA and RAD18-dependent PCNA NEDDylation increases markedly after its ubiquitination. Impairment of NEDDylation by Ubc12 knockout enhances PCNA ubiquitination and promotes PCNA-polη interaction, while up-regulation of NEDDylation by NEDD8 overexpression or NEDP1 deletion reduces the excessive accumulation of ubiquitinated PCNA, thus inhibits PCNA-polη interaction and blocks polη foci formation. Moreover, Ubc12 knockout decreases cell sensitivity to HO-induced oxidative stress, but NEDP1 deletion aggravates this sensitivity. Collectively, our study elucidates the important role of NEDDylation in the DDR as a modulator of PCNA monoubiquitination and polη recruitment.