Mycobacterial PstP impairs host RNA alternative splicing by dephosphorylation of spliceosome RBMX at S189
Tianxian Liu,
Jun‐Yu Xu,
Lei Zhao,
Yameng Fan,
Shuyu Xie,
Ke Ma,
Ying Zhou,
Minjia Tan,
Bang‐Ce Ye
Affiliations
Tianxian Liu
Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering East China University of Science and Technology Shanghai China
Jun‐Yu Xu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Lei Zhao
Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering East China University of Science and Technology Shanghai China
Yameng Fan
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Shuyu Xie
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Ke Ma
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Ying Zhou
Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering East China University of Science and Technology Shanghai China
Minjia Tan
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Bang‐Ce Ye
Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering East China University of Science and Technology Shanghai China
Abstract Mycobacterium tuberculosis (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 PLA2G7, which encodes platelet‐activating factor acetylhydrolase, resulting an increase in the mRNA levels of a transcript containing exon9 (PLA2G7‐exon9+). Importantly, PLA2G7 isoform encoded by PLA2G7‐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.
