The novel role of MEG3 in Glaesserella parasuis-infected porcine alveolar macrophages: Modulating apoptosis via MDM2-mediated ubiquitination and degradation of ILF3 to suppress CFLAR transcription.

Glaesserella parasuis (G. parasuis) is an important opportunistic pathogen that poses a threat to the swine industry, and the induction of host cell apoptosis is one of the key pathogenic mechanisms by which G. parasuis invades and damages the host. Long non-coding RNAs (lncRNAs) exert diverse and crucial biological functions in cells. Maternally expressed gene 3 (MEG3), a lncRNA widely involved in cell proliferation, apoptosis, and immune responses, has been demonstrated to be associated with G. parasuis infection. However, the function and mechanism of MEG3 in regulating G. parasuis-induced apoptosis remain unclear. In this study, we found that in the porcine alveolar macrophage cell line 3D4/21, MEG3 interacts with interleukin enhancer-binding factor 3 (ILF3) and negatively regulates the protein expression of ILF3 in the nucleus. Functional analysis showed that ILF3 suppresses G. parasuis-induced apoptosis of 3D4/21 cells, whereas MEG3 participates in regulating this apoptotic process through its interaction with ILF3. Further mechanistic studies revealed that MEG3 acts as a molecular scaffold to recruit the E3 ubiquitin ligase MDM2, enhances the interaction between MDM2 and ILF3, and thereby promotes the ubiquitination and degradation of ILF3. Moreover, ILF3 binds to the promoter of the anti-apoptotic gene CFLAR to facilitate its transcription, whereas MEG3 inhibits ILF3-mediated transcriptional activation of CFLAR, consequently regulating G. parasuis-induced apoptosis of 3D4/21 cells. This study reveals a novel mechanism by which MEG3 regulates G. parasuis-induced apoptosis of 3D4/21 cells via the MDM2/ILF3/CFLAR axis. These findings provide new insights into elucidating the molecular pathogenic mechanisms of G. parasuis.