RBMX2: A Pivotal Regulator Linking Mycobacterium bovis Infection to Epithelial-Mesenchymal Transition and Lung Cancer Progression

The emergence and progression of tuberculosis (TB) result from the intricate interplay among the pathogen, host, and environmental factors. In 2022, there were 10.6 million new TB cases reported globally, leading to 1.3 million deaths. In regions with a high prevalence of zoonotic TB, Mycobacterium bovis ( M. bovis ) accounts for approximately 10% of human TB cases. The immune evasion mechanisms and latent infections of Mycobacterium tuberculosis ( M. tb ) complicate our understanding of the host immune response to TB. This study identifies a novel host factor, RNA-binding motif protein X-linked 2 (RBMX2), which shows potential against M. bovis infection. However, the specific molecular mechanisms and roles of RBMX2 during M. bovis infection remain poorly understood. Our investigations revealed that following infection, RBMX2 was highly expressed in various cell types, including embryonic bovine lung (EBL) cells, bovine macrophage (BoMac) cells, bovine lung alveolar primary cells, and human pulmonary alveolar epithelial cells (A549). Using a multifaceted approach that included global transcriptional sequencing, proteomics, cell adhesion assays, ChIP-PCR, and Western blot analyses, we demonstrated that RBMX2 inhibits cell adhesion and tight junction formation in EBL cells while promoting the adhesion and invasion of M. bovis through the activation of the p65 pathway. Furthermore, our data suggest that RBMX2 regulates epithelial-mesenchymal transition (EMT), a process strongly associated with cancer, as indicated by our global transcriptomics, proteomics, and metabolomics analyses. To further explore the relationship between RBMX2 and cancer, we analyzed the TIMER2.0 database and found elevated expression levels of RBMX2 in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) tissues compared to normal lung tissues. This finding was corroborated by immunofluorescence validation. After constructing an M. bovis -infected BoMac-induced EBL-EMT model, we confirmed that RBMX2 contributes to EMT by activating the p65/MMP-9 pathway post-infection.

This study elucidates the role of RBMX2 as a novel host factor with potential anti-TB functions that inhibit TB-induced EMT. These insights have vital implications for the development of TB vaccines and therapeutic strategies for TB-mediated lung cancer, highlighting RBMX2 as a promising target for future research.