Research
| Title： | Fish TOLLIP manipulates ATG5 for autophagic degradation of STING to attenuate antiviral interferon responses |
|---|---|
| First author： | Tian, Meng-Ze; Wang, Yang-Yang; Cui, Bao-Jie; Xu, Xiao; Zhou, Chu-Jing; Zhang, Can; Li, Zhuo-Cong; Hong, Meng-Qian; Xu, Na; Chen, Dan-Dan; Lu, Long-Feng; Li, Shun |
| Journal： | PLOS PATHOGENS |
| Years： | 2025 |
| DOI： | 10.1371/journal.ppat.1013512 |
| Abstract： | While robust interferon (IFN) responses in fish are critical for viral clearance, dysregulated signalling can trigger detrimental hyperinflammation, necessitating precise immunoregulatory mechanisms. This study identified Toll-interacting protein (TOLLIP) as a pivotal negative regulator of IFN production in grass carp (Ctenopharyngodon idella). Upon grass carp reovirus (GCRV) infection, TOLLIP expression increases significantly in tissues and cells. Furthermore, TOLLIP overexpression reduced GCRV- and polyinosinic-polycytidylic acid (poly I:C)-induced IFN expression, whereas tollip knockdown increased the cellular IFN production capacity. TOLLIP subsequently binds and degrades STING. Further mechanistic studies revealed that TOLLIP degrades STING in a dose-dependent manner via an autophagy-lysosome-dependent pathway. Interestingly, autophagy-related protein 5 (ATG5) was found to interact with TOLLIP and reduce TOLLIP-mediated STING degradation after atg5 knockdown. In addition, TOLLIP attenuated STING-driven IFN activation and compromised antiviral efficacy. These findings demonstrate that fish TOLLIP plays a specialized regulatory role in antiviral innate immunity, balancing immune defence with homeostasis maintenance. |
