Dengue virus non-structural protein 1 suppresses megakaryopoiesis by targeting the FOSB transcription factor
This study aimed to elucidate the molecular mechanism by which Dengue virus (DENV) non-structural protein 1 (NS1), a key viral virulence factor, suppresses megakaryopoiesis, the process responsible for platelet production in the bone marrow. Severe dengue is characterized by profound thrombocytopenia; however, the contribution of secreted NS1 to bone marrow suppression remains incompletely understood. Using RNA sequencing (RNA-seq) analysis in a human erythroleukemia (HEL) cell model, we compared gene expression profiles during megakaryocytic differentiation in the presence or absence of recombinant NS1. Our analysis identified the transcription factor FOSB as a critical regulator that is significantly downregulated by NS1 during megakaryocyte differentiation. Functional studies demonstrated that NS1 inhibits megakaryocytic differentiation and polyploidization through suppression of FOSB, independent of viral replication. These findings reveal a previously unrecognized mechanism underlying DENV-induced thrombocytopenia and identify FOSB as a potential therapeutic target for mitigating thrombocytopenia and improving clinical outcomes in patients with severe dengue.