Ribonucleotide reductase subunit M2 mediates the mTOR pathway to recruit furin endoprotease and promote maturation of dengue virus

Summary: Dengue virus (DENV) maturation involves calcium-dependent endoprotease furin, which cleaves the precursor membrane (prM) into the M protein in the trans-Golgi network, facilitating the release of infectious virus. Here, we demonstrate that ribonucleotide reductase subunit M2 (RRM2) recruits furin to mediate the cleavage of the DENV prM protein. Silencing of RRM2 reduced furin expression, leading to the accumulation of uncleaved prM in infected cells, increased intracellular DENV RNA, and diminished infectious virus titers in the supernatant. DENV infection prompted colocalization and interaction between RRM2 and furin in hepatoma cells and liver tissues of infected mice, with enhancement of RRM2 expression and furin stability. Silencing RRM2 impeded the effects of mammalian target of rapamycin (mTOR), leading to decreased furin expression. Additionally, mTOR overexpression reduced uncleaved prM and intracellular viral RNA while increasing furin levels in DENV-infected cells. These findings highlighted a DENV maturation process, which is fine-tuned by the RRM2-mTOR-mediated pathway.