FGF8-mediated TRIM16 regulation promotes K48-linked ubiquitination and degradation of RIG-I to facilitate Influenza a virus immune evasion.

Influenza A virus (IAV) exhibits notable genetic diversity and cross-species transmission capacity, posing a continuous challenge to public health. Elucidating host immune regulatory mechanisms is crucial for identifying new antiviral targets that can overcome viral resistance. Here, using human A549 lung epithelial cells as the primary model, we identify fibroblast growth factor 8 (FGF8) as a crucial host factor whose expression is significantly elevated during infection by various IAV subtypes (including H1N1, H13N2, H9N2, and PR8). Through gain- and loss-of-function assays, we demonstrate that FGF8 specifically enhances viral replication at the post-entry stage by suppressing interferon-beta (IFN-β) and interferon-stimulated genes (ISGs) expression. Mechanistically, FGF8 reduces retinoic acid-inducible gene I (RIG-I) protein stability via K48-linked polyubiquitination without affecting its mRNA levels. Ubiquitination identifies Lysine 258 (K258) on RIG-I as the essential modification site; notably, a K258R mutation prevents RIG-I degradation and restores IFN-β induction. Furthermore, TurboID-based proximity labeling captures the close spatial association of FGF8 with both tripartite motif containing 16 (TRIM16) and RIG-I, revealing that FGF8 acts as a molecular scaffold to recruit the E3 ligase TRIM16 to RIG-I. Consistently, TRIM16 silencing replicates the antiviral effects of FGF8 knockdown. Collectively, our findings demonstrate that FGF8 recruits TRIM16 to degrade RIG-I, thereby facilitating viral immune evasion. Disrupting this interaction offers a potential avenue for anti-influenza A virus intervention.