Attenuate host susceptibility to respiratory virus invasion by inhibiting interactions between host proteins SLC16A3 and AP1G1.

Modulating cell endocytosis activity to reduce host susceptibility to virus represents a promising strategy for antiviral drug development. In this study, we reveal that lactate transporter SLC16A3 is a critical host factor for reducing diverse virus invasion. By performing metabolomics, proteomics, and thermal proteome profiling experiments, AP1G1, a pivotal protein involved in cellular endocytosis, was indiscriminately screened as a chaperone of SLC16A3. SLC16A3 decides the membrane enrichment of AP1G1 by protein interaction, thereby influencing host susceptibility to diverse viruses. This conclusion was further validated in SLC16A3 knocked-down cells, which indicated a broad-spectrum target for anti-virus drug development to recede virus entry by blocking the interaction between AP1G1 and SLC16A3. This conclusion has been validated with a patent medicine Shufengjiedu (SFJD). SFJD exhibits strong effect in decreasing the susceptibility of host cells to viral infections. Molecularly, SFJD administration results in disrupting the interaction between SLC16A3 and AP1G1 and reduced membrane localization of AP1G1. Consequently, it achieves a receded endocytosis activity of host cells on viral particles. This provides evidence for the practicability of the SLC16A3-AP1G1 strategy. Taken together, the regulation on the SLC16A3-AP1G1 interaction represents a broad-spectrum and practicable antiviral strategy. This study offers insights into a novel approach for inhibiting viral infections through the alteration of host susceptibility and advances the idea for antiviral drug development.IMPORTANCEWe have discovered that a broad-spectrum antiviral strategy, highlighting the lactate transporter SLC16A3 as a critical determinant of host cell susceptibility to viruses. SLC16A3 was found to interact with AP1G1, which is a pivotal protein involved in cellular endocytosis. Disrupting the interaction between AP1G1 and SLC16A3 leads to reduced membrane localization of AP1G1, thereby reducing the host cell endocytosis of viral particles. Importantly, we found that the patent medicine Shufengjiedu (SFJD can significantly reduce the susceptibility of host cells to viral infection through this mechanism, providing evidence for the practicability of SLC16A3-AP1G1 strategy. Taken together, the modulation on the SLC16A3-AP1G1 interaction represents a broad-spectrum and practicable antiviral mechanism. This study offers novel insights into strategies for inhibiting viral infections through the alteration of host susceptibility and advances the idea for antiviral drug development.