Mycobacterial Pstp Impairs Host RNA Alternative Splicing by Dephosphorylation of Spliceosome RBMX at S189

Mycobacterium tuberculosis (Mtb) infection can widely affect host signal transduction and protein function. Recent studies have revealed that Mtb virulence factors could regulate host immune activation and promote intracellular survival of the pathogen. However, no systematic research has been conducted on Mtb infection. Here, we analyzed mycobacteria-infected cells using multi-omics (proteomics, phosphoproteomics, transcriptomics, and interactomics) and observed that mycobacteria could regulate host alternative splicing by decreasing spliceosomes phosphorylation level. Using phosphoproteomics and interactomics, we connected decreased host phosphorylation with mycobacterial serine/threonine protein phosphatase PstP and observed that Pstp can regulate host Pla2g7 gene alternative splicing by dephosphorylating the spliceosome RBMX S189 site. Further studies showed that PLA2G7 exon9 including rather than excluding form, promotes the inflammatory response. In conclusion, our findings revealed the global landscape and Pstp functions during Mtb infection, which could lead to a deeper understanding of Mtb-host interactions.