A <i>Mycobacterium tuberculosis</i> secreted virulence factor Rv1435c/hsr1 disrupts host snRNP biogenesis
Abstract
Transcriptional adaptation drives the host responses to Mycobacterium tuberculosis ( Mtb ) infection. However, Mtb alters host RNA splicing to quench host antibacterial responses, the mechanism for which remains unknown. Here, we report a mechanism whereby a secreted Mtb protein interferes with the biogenesis of key spliceosomal components. A high-throughput yeast-2-hybrid screen identified several Mtb -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 Mtb Rv14345c/hsr1 facilitates direct interaction between Mtb 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 Mtb infection. The Δ hsr1 strain shows compromised growth during ex vivo infection in macrophages and in vivo infection in mice. Tissue sections from the WT Mtb or Δhsr1 -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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (22)
Komal Chauhan
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Dipanwita Datta
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Yogita Kapoor
Nishat Passricha
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Ravi Dutt
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Naresh Arora
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Mrinmoy Das
Department of Chemistry, Worcester Polytechnic Institute, Worcester, MA, USA.
Kavya Rao
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Lakshyaveer Singh
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Arunima Gautam
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Raman Deep Sharma
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Binayak Sarkar
National Institute of Immunology, Aruna Asaf Ali Marg
Mohit Yadav
National Institute of Immunology, Aruna Asaf Ali Marg
Basanti Malakar
National Institute of Immunology, Aruna Asaf Ali Marg
Haroon Kalam
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg
Prince Saini
Department of Biological Sciences, Indian Institute of Science Education and Research Mohali
Lalita Mehra
Department of Pathology, All India Institute of Medical Sciences
Prasenjit Das
Department of Chemistry, Functional Materials
Vineet Ahuja
Amit Singhal
A*STAR Infectious Diseases Labs (A*STAR ID labs), Agency for Science, Technology and Research (A*STAR)
Vinay Nandicoori
Centre for Cellular and Molecular Biology
Dhiraj Kumar
Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg