Abstract
The accurate assembly of the ribonucleoprotein (RNP) complex is fundamental for the replication and transcription of rhabdoviruses, which are known for their broad pathogenic impact. A novel 119-amino-acid protein, NLRP12-119aa is identified, encoded by the circular RNA circNLRP12, that effectively disrupts the formation of rhabdovirus RNP complexes through two distinct mechanisms and significantly reduces their replication. NLRP12-119aa exhibits a strong affinity for the conserved 18-nucleotide sequence at the start of the leader RNA of rhabdoviruses VSV, SCRV, and RABV, outcompeting their native N protein interactions, thereby disrupting the assembly of RNP complexes and inhibiting viral replication. NLRP12-119aa exerts anti-rhabdoviral effects by directly binding to the viral N protein, leading to its destabilization and accelerated degradation, and consequently hindering the formation of the viral RNP complex. To assess the therapeutic potential of circNLRP12 against rhabdovirus infections, a zebrafish model of VSV infection is established and noted a substantial reduction in viral load after-treatment with circNLRP12, as well as the recovery of spleen's to a normalized state from its previously enlarged and hemorrhagic state. Collectively, these findings elucidate a novel dual anti-RNP assembly strategy mediated by NLRP12-119aa, offering valuable insights for further exploration and clinical management of rhabdoviral infections.