Protein RBMX2 links bovine TB infection to cell changes and lung cancer

Tuberculosis remains a major global health problem, and in some regions a related bacterium, Mycobacterium bovis, causes a significant share of human TB cases. To better understand how the host responds to M. bovis and why infection can sometimes be linked to later problems in the lung, Aizhen Guo led a study that searched for host factors changed by infection. The team focused on a protein called RNA-binding motif protein X-linked 2 (RBMX2), which had not previously been well studied in this context. They first observed that RBMX2 levels rise after cells encounter M. bovis. The increase was seen in several different cell types, including embryonic bovine lung (EBL) cells, bovine macrophage (BoMac) cells, bovine pulmonary alveolar primary cells, and human alveolar epithelial cells (A549). Because RBMX2 is an RNA-binding protein and because TB involves complex interactions between pathogen and host tissues, the researchers set out to determine what RBMX2 does during infection and whether it could help explain how infection may encourage changes in lung cells linked to cancer.

To map the effects of RBMX2, the team used a mix of molecular and cellular methods: global transcriptomic sequencing, proteomic profiling, cell adhesion assays, ChIP-PCR, Western blotting, and immunofluorescence staining. They also performed integrated analyses combining transcriptomic, proteomic, and metabolomic data and queried the TIMER2.0 database for expression in human tumors. These experiments showed that RBMX2 is significantly upregulated after infection in EBL, BoMac, bovine pulmonary alveolar primary cells, and A549. In EBL cells, RBMX2 reduced cell adhesion and weakened tight junctions, changes that made it easier for M. bovis to stick to and invade cells. Mechanistically, RBMX2 activated the p65 signaling pathway to promote bacterial adhesion and invasion. Integrated data pointed to a broader role for RBMX2 in regulating epithelial-mesenchymal transition (EMT), a process linked to cancer progression. TIMER2.0 and immunofluorescence staining revealed higher RBMX2 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues. Using an M. bovis-infected BoMac-induced EBL-EMT model, the authors showed RBMX2 drives EMT via the p65/MMP-9 pathway, and they validated EMT involvement in human H1299 lung cancer cells.

Taken together, these findings position RBMX2 as a novel host factor that both helps M. bovis infect lung cells and promotes infection-induced epithelial-mesenchymal transition. That dual role links an immune response element to physical changes in epithelial cells that are known to be associated with cancer progression. By showing RBMX2 is upregulated across multiple cell types and by tracing a pathway from RBMX2 through p65 and MMP-9 to EMT, the study provides a molecular explanation for how infection could contribute to later changes in lung tissue. The work stops short of proving a direct cause of human lung cancer, but it supplies concrete targets and pathways for follow-up. Importantly, the study suggests RBMX2 could be explored as a potential target when designing new TB vaccines or therapies aimed at preventing the long-term lung consequences of infection, including TB-associated lung cancer.