Nuclear targeting of the betanodavirus B1 protein via two arginine-rich domains induces G1/S cell cycle arrest mediated by upregulation of p53/p21

• Published in: Scientific reports 2018-02, Vol.8 (1), p.3079-12, Article 3079
• Main Authors: Su, Yu-Chin, Reshi, Latif, Chen, Lei-Jia, Li, Wei-Han, Chiu, Hsuan-Wen, Hong, Jiann-Ruey
• Format: Article
• Language: English
• Subjects: 13; 13/31; 13/44; 38; 38/1; 38/109; 38/23; 38/35; 38/70; 38/77; 631/326/596/2557; 692/308/153; Arginine; Cell cycle; Cell survival; Cyclin D1; Cyclin-dependent kinase 4; Cyclin-dependent kinase inhibitor p21; Eukaryotes; GTP-binding protein; Humanities and Social Sciences; Localization; MDM2 protein; multidisciplinary; p53 Protein; Protein B; Proteins; Science; Science (multidisciplinary); Up-regulation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-21340-x

The molecular functions of betanodavirus non-structural protein B and its role in host cell survival remain unclear. In the present study, we examined the roles of specific nuclear targeting domains in B1 localization as well as the effect of B1 nuclear localization on the cell cycle and host cell survival. The B1 protein of the Red spotted grouper nervous necrosis virus (RGNNV) was detected in GF-1 grouper cells as early as 24 hours post-infection (hpi). Using an EYFP-B1 fusion construct, we observed nuclear localization of the B1 protein (up to 99%) in GF-1 cells at 48 hpi. The nuclear localization of B1 was mediated by two arginine-rich nuclear targeting domains (B domain: 46 RRSRR 51 ; C domain: 63 RDKRPRR 70 ) and domain C was more important than domain B in this process. B1 nuclear localization correlated with upregulation of p53 and p21 (wef1/cip1) ; downregulation of Cyclin D1, CDK4 and Mdm2; and G1/S cell cycle arrest in GF-1 cells. In conclusion, nuclear targeting of the RGNNV B1 protein via two targeting domains causes cell cycle arrest by up-regulating p53/p21 and down-regulating Mdm2, thereby regulating host cell survival.