The integrin protein ITGβ1 effectively suppresses porcine epidemic diarrhea virus replication through facilitating MDA5 oligomerization and subsequent activation of the type I interferon signaling pathway

ABSTRACT Integrins are cell surface adhesion molecules. They bridge the intracellular and extracellular environments, enabling bidirectional transmembrane signaling and regulating immune responses. However, it remains unclear whether integrin protein β1 (ITGβ1) is involved in innate immune responses. In our previous study, we demonstrated that porcine epidemic diarrhea virus (PEDV) can induce type I interferon (IFN-I) production. In this study, we observed that ITGβ1 expression is rapidly induced following PEDV infection and further established that PEDV infection primarily promoted ITGβ1 expression through upregulation of the transcription factor c-Myc. We hypothesized that ITGβ1 might be involved in PEDV-induced innate immune responses through IFN-I production. Our investigation revealed ITGβ1 overexpression promotes the phosphorylation and subsequent nuclear translocation of both interferon regulatory factor 3 (IRF3) and NF-κB, thereby enhancing SeV-induced IFN-β promoter activity. Furthermore, we showed that ITGβ1 functions as an activator in the melanoma differentiation-associated protein 5 (MDA5)-mediated IFN-I signaling pathway. More importantly, we demonstrated that ITGβ1 is critically involved in PEDV-induced IFN-I antiviral responses. Mechanistically, ITGβ1 facilitates MDA5 oligomerization by specifically interacting with its caspase activation and recruitment domain (CARD), thereby enhancing dsRNA-recruitment capacity. In summary, the findings of this study indicate that ITGβ1 acts as an activator of the MDA5-dependent IFN-I antiviral innate immune response and positively regulates the MDA5-mediated RIG-I-like receptor signaling pathway. IMPORTANCE Porcine epidemic diarrhea virus (PEDV), an alpha coronavirus, severely impacts newborn piglets, leading to acute manifestations including vomiting, diarrhea, dehydration, and high mortality rates in suckling piglets. These consequences have devastating implications for the global swine industry. Within the host’s innate antiviral response, RIG-I-like receptors (RLRs) are critical for the activation of the interferon signaling pathway. Integrin proteins, known for their role in regulating bidirectional signal transduction across the cell membrane, are associated with numerous viral infections. In this study, utilizing PEDV as an infection model, we demonstrated that overexpression of ITGβ1 suppresses PEDV replication, while knockdown of ITGβ1 expression enhances it. Additionally, ITGβ1 significantly augments PEDV-induced type I interferon production in host cells. We further elucidated that ITGβ1 interacts with the 2CARD region of MDA5, promoting MDA5 oligomerization and the transmission of activation signals. These findings establish ITGβ1 as a positive regulatory factor in MDA5-mediated RLR signaling pathway. These findings not only identify ITGβ1 as a novel host antiviral protein against PEDV but also reveal, for the first time, a previously unrecognized function of ITGβ1 in the cellular innate antiviral immune response.