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

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.