NSP1 of Alongshan virus antagonizes type I interferon responses by promoting STUB1-mediated degradation of RIG-I

Abstract Emerging tick-borne viruses have become a significant public health concern due to their association with severe human illnesses. Among these, Alongshan virus (ALSV), a segmented RNA virus first identified in northeastern China, has been linked to febrile illness, presenting with fever, headache, myalgia, and, in severe cases, multi-organ failure. Despite its clinical relevance, the mechanisms by which ALSV evades host immune defenses remain poorly understood. Here, we identify NSP1, a nonstructural protein of ALSV, as a potent inhibitor of type I interferon (IFN-I) production, specifically targeting the RIG-I signaling pathway. Mechanistically, NSP1 binds to RIG-I, preventing its interaction with MAVS and facilitating RIG-I’s STUB1-mediated K48-linked polyubiquitination and subsequent proteasomal degradation. By disrupting the RIG-I/MAVS complex and promoting the targeted degradation of RIG-I, NSP1 effectively suppresses the IFN-I response, a critical component of the host antiviral defense. Our study provides a dual mechanism through which NSP1 impairs immune detection, highlighting its role in immune evasion and viral persistence. These findings not only advance our understanding of ALSV pathogenesis but also offer a potential therapeutic target for antiviral interventions, shedding light on broader strategies employed by viruses to subvert host immune responses. Graphical Abstract Upon ALSV infection, the viral NSP1 protein facilitates the recruitment of the E3 ubiquitin ligase STUB1, which ubiquitinates and promotes the degradation of the key RNA sensor RIG-I. Additionally, NSP1 disrupts the interaction between RIG-I and MAVS, thereby blocking downstream signal transduction and suppressing interferon production. A model of RIG-I-mediated crosstalk between ALSV and IFN.