A Mycobacterium tuberculosis secreted virulence factor disrupts host snRNP biogenesis

Alternative splicing is a fundamental eukaryotic process that fine-tunes cellular responses post-transcriptionally. Mycobacterium tuberculosis (Mtb) infection of human macrophages triggers extensive dysregulation of host alternative splicing (AS) to alter the host responses. However, the mechanism behind this remains unknown. Here, we present an unexpected mechanism exploited by the Mtb to achieve the same. We identify several bacterial secretory proteins that interact with the host splicing factors (SFs) and alter select RNA splicing events in vitro , in cell and during ex vivo infections. We show bacterial proteins disrupt AS by impairing Small nuclear ribonucleoprotein (snRNP) biogenesis, primarily by interacting with and sequestering U5snRNA and SNRPF, key spliceosome constituents. These interactions are driven, in part, by one of the identified Mtb proteins, Hsr1, whose access to the host cytosol is ESX1-dependent. The Mtb ι1hsr1 is unable to interact and sequester U5snRNA or SNRPF and fails to alter host AS. Consequently, Mtb ι1hsr1 shows compromised survival and pathogenesis in macrophages and mice. Lungs of infected mice show distinct SNRPF staining, which is hsr1 dependent. Similar distinctive SNRPF staining is also noted in human tuberculous granulomas. Moreover, monocytes from tuberculosis patients show a substantial splicing dysregulation indicating splicing defects as a key determinant behind systemic tuberculosis pathology. We propose mycobacterial exploitation of the evolutionarily conserved mechanism of snRNP biogenesis, aided its adaptation for human pathogenesis and provides a unique therapeutic opportunity. ### Competing Interest Statement The authors have declared no competing interest.