Abstract

Classical swine fever virus (CSFV) establishes efficient infection by manipulating host factors and intracellular pathways to support viral replication. The host lectin mannose-binding 1 (LMAN1) is a cargo receptor that is involved in the assembly and morphogenesis of several RNA and DNA viruses. However, the function and potential mechanism of LMAN1 in CSFV infection remain elusive. Here, we investigated the LMAN1 expression pattern in CSFV-infected pigs and PK-15 cells, showing upregulation of the protein after CSFV infection. LMAN1 knockdown and overexpression further demonstrated that LMAN1 expression was required for efficient CSFV proliferation. Mechanistically, LMAN1 directly associates with the viral RNA-dependent RNA polymerase NS5B via its carbohydrate recognition domain (CRD), promoting efficient viral replication complex formation. Beyond its vital role in viral RNA replication, LMAN1 also functions as a negative regulator of antiviral signaling. Transcriptomic analyses revealed that LMAN1 deficiency hyperactivates the RIG-I-like receptor (RLR)-MAVS pathway, and further studies confirmed that loss of LMAN1 enhances IRF3 and NF-κB p65 phosphorylation, as well as interferon-β production in response to CSFV. MAVS knockdown reversed the interferon signaling hyperactivation caused by LMAN1 deficiency, and LMAN1 rescue experiments showed that the CRD domain is indispensable for suppression of interferon responses, revealing that LMAN1 modulates antiviral responses via the RLR-MAVS pathway relying on its CRD domain. Overall, our findings uncover LMAN1 as a previously unrecognized host determinant with dual function in CSFV replication and immune evasion, offering new insights into virus-host interactions and revealing a potential antiviral target.