Mycobacterial PstP impairs host RNA alternative splicing by dephosphorylation of spliceosome RBMX at S189

<i>Mycobacterium tuberculosis</i> (Mtb) infection significantly alters host cellular signaling and protein functions, facilitating immune evasion and intracellular survival. However, the molecular mechanisms underlying these interactions remain incompletely characterized. Here, we employed a multi-omics strategy, including proteomics, phosphoproteomics, transcriptomics and interactomics, to investigate the impact of Mtb infection on host cellular processes. Our study revealed that mycobacteria modulate RNA alternative splicing in host cells by reducing the phosphorylation levels within the spliceosome complex. We identified the serine/threonine protein phosphatase (PstP) as a key effector, dephosphorylating the spliceosome RNA-binding motif protein (RBMX) at the serine 189 site (S189). This modification influences the alternative splicing of <i>PLA2G7</i>, which encodes platelet-activating factor acetylhydrolase, resulting an increase in the mRNA levels of a transcript containing exon9 (<i>PLA2G7-</i>exon9+). Importantly, PLA2G7 isoform encoded by <i>PLA2G7-</i>exon9+, in contrast to the isoform lacking exon9, acquires the ability to potentiate inflammatory responses. Collectively, our findings not only provide a comprehensive view of Mtb-induced host regulatory networks but also elucidate a role for PstP in controlling a critical mediator of alterative splicing during infection.