IFN‐stimulated metabolite transporter ENT3 facilitates viral genome release

Abstract

An increasing amount of evidence emphasizes the role of metabolic reprogramming in immune cells to fight infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of equilibrative nucleoside transporter 3 (ENT3, encoded by solute carrier family 29 member 3, Slc29a3 ) is part of the innate immune response, which is rapidly upregulated upon pathogen invasion. The transcription of Slc29a3 is directly regulated by type I interferon‐induced signaling, demonstrating that this metabolite transporter is an interferon‐stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS‐CoV‐2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of Slc29a3 expression is sufficient to significantly decrease viral replication in vitro and in vivo . Our study reveals that ENT3 is a pro‐viral ISG co‐opted by some viruses to gain a survival advantage. image ENT3 is an IFN‐stimulated metabolite transporter in macrophages that facilitates viral genome release. Suppression of ENT3 expression is sufficient to decrease viral replication both in vitro and in vivo . ENT3 is a fast‐responding metabolite transporter upon pathogen insults. ENT3 is an interferon‐stimulated gene whose expression is regulated by the type I IFN‐IFNAR axis. Viruses have co‐evolved with the host and take advantage of ENT3 for their genome release and their replication.