TGEV infection activates pro‑inflammatory signaling via the YY1/HSP40/NF‑κB pathway in intestinal epithelial cells and organoids

Abstract

Transmissible gastroenteritis virus (TGEV) is a porcine enteropathogenic coronavirus that causes severe intestinal inflammation and diarrhea in pigs, leading to substantial economic losses to the swine industry worldwide. Inflammation is a major cause of death in pigs infected with TGEV. However, the role of host-mediated inflammatory responses in TGEV pathogenesis remains poorly understood. Here, we report for the first time that the heat shock protein HSP40 (DNAJB6) is highly expressed in the jejunum and ileum of Wuzhishan pigs during TGEV infection, and that its transcription is activated by the transcription factor YY1. Gain- and loss-of-function experiments revealed that HSP40 enhances both the inflammatory response and TGEV replication by modulating NF-κB signaling. Mechanistically, HSP40 facilitates the recruitment of β-TRCP, an E3 ubiquitin ligase of IκB, promoting its interaction with IκB and subsequent proteasomal degradation. Under basal conditions, IκB binds to and sequesters p65 (RelA) in the cytoplasm, preventing its nuclear translocation and transcriptional activity. During TGEV infection, HSP40-mediated degradation of IκB releases p65, enabling its nuclear translocation and the transcriptional activation of multiple inflammatory genes. Furthermore, β-TRCP was found to be essential for HSP40-mediated production of inflammatory cytokines. Collectively, these findings uncover a pivotal role for HSP40 in regulating inflammation and viral replication during TGEV infection, and suggest that targeting HSP40 may represent a promising therapeutic approach against TGEV.