A <i>Mycobacterium tuberculosis</i> secreted virulence factor Rv1435c/hsr1 disrupts host snRNP biogenesis.

Abstract

Transcriptional adaptation drives the host responses to <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) infection. However, <i>Mtb</i> alters host RNA splicing to quench host antibacterial responses, the mechanism for which remains unknown. Here, we report a mechanism whereby a secreted <i>Mtb</i> protein interferes with the biogenesis of key spliceosomal components. A high-throughput yeast-2-hybrid screen identified several <i>Mtb</i>-secreted proteins interacting with the host RNA splicing factors (SFs). Through custom-designed in-cell assays, we show that one of those proteins, Rv1435c/hsr1 (host splicing regulator 1), targets specific exon-skipping events. The <i>Mtb</i> Rv14345c/hsr1 facilitates direct interaction between <i>Mtb</i> phagosomes and U5 snRNA and SNRPF, key components of the snRNPs. Genetic deletion of Rv1435c/hsr1 reverses the specific exon-skipping events caused by WT <i>Mtb</i> infection. The Δ<i>hsr1</i> strain shows compromised growth during ex vivo infection in macrophages and in vivo infection in mice. Tissue sections from the WT <i>Mtb</i> or <i>Δhsr1</i>-infected mice showed significant hsr1-dependent SNRPF staining, a phenomenon also noted in the human intestinal tuberculosis (ITB) biopsies. Thus, hsr1 is a virulence factor that disrupts host snRNP biogenesis for pathogenesis. The splicing regulators from the host and pathogen are novel targets for antituberculosis therapy.