LXN exerts antiviral effects by inhibiting the binding of HMGB1 to the viral genome.

Latexin (LXN) is a key carboxypeptidase inhibitor involved in multiple human diseases, including metabolic disorders and cancer. Our previous study has demonstrated the antiviral activity of LXN against Hepatitis C Virus (HCV) and Vesicular Stomatitis Virus (VSV), however, the mechanism remains incompletely understood. Here, we show that, besides HCV and VSV, LXN can also inhibit the replication of Newcastle Disease Virus (NDV) and Herpes Simplex Virus-1 (HSV-1), suggesting a universal antiviral activity of LXN. Mechanistically, the inhibitory effects of LXN are a consequence of the impairment of High Mobility Group Box 1 (HMGB1)-mediated viral escape, rather than viral attachment, entry, translation or the innate immunity-mediated antiviral response. LXN neither affects the expression of HMGB1 nor interacts with HMGB1, but suppresses the activity of HMGB1 to bind to viral genome. Further study demonstrates that LXN is a nucleic acid-binding protein and competes with HMGB1 to bind to viral genome, thereby suppression of the viral replication. Moreover, in vivo analysis demonstrates that Lxn-knockdown mice exhibit more susceptible to viral infection than wild type mice. Overall, our study highlights the novel function of LXN that exhibits antiviral activity through capturing the viral genome that binds to HMGB1, which will provide a new insight on understanding host-virus interaction and a potential target for clinical treatment of infectious diseases.