Work

TREX1 enables viral entry in intestinal epithelia via immunity-independent control of endocytosis

Year: 2025

Type: article

Abstract: The endocytic machinery is essential for viral entry and material absorption, yet its regulatory mechanisms remain incompletely understood. Here, we report an unexpected function of the host exonuclease three-prime repair exonuclease 1 (TREX1) in promoting enterovirus A71 (EV-A71) infection independently of immune modulation. Our results reveal that TREX1 deficiency in intestinal cells does not activate innate immunity but impairs EV-A71 replication, primarily by blocking viral entry. Mechanistically, TREX1 silencing downregulates key endocytic factors, including WASF1, thereby inhibiting viral internalization. Disease-associated TREX1 mutations were found to disrupt this pro-endocytic function. Furthermore, we demonstrate that TREX1-dependent endocytosis is critical for dextran uptake, highlighting its broader role in nutrient absorption. Subsequently, we employed a TREX1 inhibitor, TREX1-IN-1, which suppresses viral infection without eliciting innate immune responses. Our study uncovers an immunity-independent role for TREX1 in regulating endocytosis, provides insights into viral entry and intestinal nutrient uptake, and further establishes TREX1 as a druggable target for antiviral therapy.

Source: Cell Reports

DOI: 10.1016/j.celrep.2025.116611