PEDV envelope protein promotes viral replication by remodeling host iron homeostasis via the TRIM28-KLF15-FPN axis.

UNLABELLED: Porcine epidemic diarrhea virus (PEDV), a member of the Alphacoronavirus genus, causes severe enteric disease with up to 100% mortality in suckling piglets. Iron is an essential micronutrient for the replication of various pathogens, including viruses, which hijack host iron resources to support their proliferation. SLC40A1 encodes ferroportin (FPN), the only known iron exporter in mammals and a key target for pathogens to manipulate host iron homeostasis. However, whether coronaviruses exploit this mechanism remains unknown. Here, we demonstrate that PEDV infection disrupts host iron homeostasis through the KLF15-FPN regulatory axis, resulting in suppressed FPN expression, intracellular iron accumulation, and enhanced viral replication. Mechanistically, the PEDV envelope (E) protein induces cytoplasmic aggregation of Kruppel-like factor 15 (KLF15) through its PDZ-binding motif (PBM), promoting tripartite motif-containing protein 28 (TRIM28)-dependent K63-linked ubiquitination and autophagy-lysosomal degradation of KLF15 at lysine 339 (K339), thereby suppressing KLF15-mediated transcriptional activation of SLC40A1. Our findings uncover a novel iron hijacking strategy by which PEDV remodels host iron homeostasis through the KLF15-FPN regulatory axis, providing new insights into coronavirus-host interactions and potential antiviral intervention strategies. IMPORTANCE: Porcine epidemic diarrhea virus (PEDV) causes a highly contagious enteric disease, posing a persistent threat to global swine production. Iron serves as a critical cofactor in numerous host and viral enzymatic processes, and profoundly influences viral infection outcomes. Ferroportin (FPN) is currently the only known iron excretory protein in mammals and has emerged as a key regulator of host iron homeostasis that can be exploited by pathogens. However, whether and how coronaviruses employ host iron regulatory pathways to remodel iron homeostasis remains unclear. Here, we reveal that PEDV E protein induces intracellular iron accumulation via the TRIM28-KLF15-FPN signaling axis, uncovering a novel function of this viral protein. This study advances our understanding of PEDV pathogenesis and highlights potential opportunities for developing anti-coronavirus strategies targeting host iron regulation.