Research
| Title： | Zebrafish CD44a variants suppress antiviral immunity through regulation of RIG-I ubiquitination and degradation |
|---|---|
| First author： | Cao, Lu; Chang, Ming Xian |
| Journal： | FISH & SHELLFISH IMMUNOLOGY |
| Years： | 2025 |
| DOI： | 10.1016/j.fsi.2025.110442 |
| Abstract： | Viral infections represent a major threat to host survival, with type I interferon (IFN-I) signaling serving as a central antiviral defense mechanism. The RIG-I-like receptor RIG-I detects viral RNA to initiate IFN-I production, yet the post-translational mechanisms regulating its activity remain poorly understood in teleost. While zebrafish CD44a, a cell adhesion molecule, protects against bacterial infections, its role in viral immunity-specifically in modulating RIG-I-mediated IFN-I signaling-has not yet been elucidated. This study characterizes the functions of zebrafish CD44a splice variants (CD44a_tv1 and CD44a_tv2) during Spring viremia of carp virus (SVCV) infection. Ectopic expression of CD44a variants enhanced viral replication and larval mortality, whereas CD44a deficiency reduced viral load and improved survival. Mechanistically, CD44a variants promoted K48-linked polyubiquitination and proteasomal degradation of RIG-I while inhibiting K63-linked activation-related ubiquitination, disrupting RLR pathway activation. Direct physical interaction between CD44a variants and RIG-I was confirmed via co-immunoprecipitation and confocal microscopy, demonstrating CD44a variants directly bind to RIG-I to facilitate RIG-I degradation and suppress IFN-I responses. These findings reveal a novel role for CD44a in antiviral immunity through dual regulation of RIG-I ubiquitination, highlighting its context-dependent duality-protecting against bacteria but exacerbating viral pathogenesis. Inhibiting the pro-viral pathogenic activity of CD44a while preserving or augmenting its anti-bacterial protective function thereby establishes promising strategies for targeted therapies against pathogen-specific infectious diseases. |
