Swine acute diarrhea syndrome coronavirus (SADS-CoV), an emerging alphacoronavirus, leads to fatal diarrhea in piglets and exhibits broad cross-species transmission potential. Bone marrow stromal cell antigen 2 (BST2) is an IFN-induced host protein known to restrict a wide range of enveloped viruses. Previous studies have shown that BST2 inhibits Porcine epidemic diarrhea virus (PEDV) replication through the selective autophagy pathway, suggesting a novel mechanism for its antiviral activity. Given that SADS-CoV and PEDV are phylogenetically related alphacoronaviruses, we hypothesized that BST2 may employ a similar mechanism to antagonize SADS-CoV infection.

To test this hypothesis, we employed TurboID-based proximity labeling combined with co-immunoprecipitation and Western blot analysis. Our results demonstrated that BST2 binds to the SADS-CoV nucleocapsid (N) protein and promotes its degradation, resulting in a significant reduction in viral replication. Further virological assays showed that overexpression of BST2 significantly reduced viral titers, whereas BST2 knockout enhanced viral replication.

These findings establish BST2 as a key host restriction factor against SADS-CoV and reveal a novel antiviral mechanism targeting the viral nucleocapsid. This work advances our understanding of innate immune defenses against coronaviruses and highlights BST2’s potential as a target for developing interventions aimed at enhancing antiviral responses in swine and mitigating zoonotic risks.