YTHDF2 promotes m6A-modified HSPA2 translation to restrict Newcastle Disease Virus

Newcastle disease virus (NDV), a highly contagious avian pathogen, causes devastating economic losses in poultry worldwide, yet the role of epitranscriptomic regulators in its pathogenesis remains poorly defined. Here we demonstrate that the m6A reader protein YTHDF2 functions as a potent antiviral effector against NDV. Through integrated functional genomics and multi-omics approaches, we establish that YTHDF2 deficiency significantly enhances NDV replication, while its overexpression suppresses viral propagation. Temporal transcriptomics and machine learning algorithms converged on HSPA2, ATF3, and IRF9 as high-confidence YTHDF2-regulated targets during infection, with HSPA2 emerging as the principal mechanistic mediator. Mechanistically, YTHDF2 directly binds m6A-modified sites within the HSPA2 coding sequence to augment its translational efficiency, as validated by RNA immunoprecipitation, isothermal titration calorimetry, and m6A-modified reporter assays. HSPA2 overexpression reduced NDV nucleoprotein levels by 68-74%, establishing its direct antiviral function. Crucially, this YTHDF2-HSPA2 axis operates independently of classical innate immune pathways, as transcriptomics revealed intact induction of antiviral genes in YTHDF2-knockout cells. Our findings unveil a previously unrecognized epitranscriptome-governed antiviral strategy wherein YTHDF2 amplifies host defense through selective translational enhancement of m6A-modified effector transcripts. This paradigm extends beyond canonical RNA decay functions of YTHDF2 and identifies the HSPA2 chaperone as a novel restriction factor against paramyxoviruses, offering new avenues for targeted antiviral interventions.