A Novel Protein NLRP12‐119aa that Prevents Rhabdovirus Replication by Disrupting the RNP Complex Formation

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.