title: The Psp system of Mycobacterium tuberculosis integrates envelope stress-sensing and envelope-preserving functions.
abstract: The bacterial envelope integrates essential stress-sensing and adaptive functions; thus, envelope-preserving functions are important for survival. In Gram-negative bacteria, envelope integrity during stress is maintained by the multi-gene Psp response. Mycobacterium tuberculosis was thought to lack the Psp system since it encodes only pspA and no other psp ortholog. Intriguingly, pspA maps downstream from clgR, which encodes a transcription factor regulated by the MprAB-σ(E) envelope-stress-signaling system. clgR inactivation lowered ATP concentration during stress and protonophore treatment-induced clgR-pspA expression, suggesting that these genes express Psp-like functions. We identified a four-gene set - clgR, pspA (rv2744c), rv2743c, rv2742c - that is regulated by clgR and in turn regulates ClgR activity. Regulatory and protein-protein interactions within the set and a requirement of the four genes for functions associated with envelope integrity and surface-stress tolerance indicate that a Psp-like system has evolved in mycobacteria. Among Actinobacteria, the four-gene module occurred only in tuberculous mycobacteria and was required for intramacrophage growth, suggesting links between its function and mycobacterial virulence. Additionally, the four-gene module was required for MprAB-σ(E) stress-signaling activity. The positive feedback between envelope-stress-sensing and envelope-preserving functions allows sustained responses to multiple, envelope-perturbing signals during chronic infection, making the system uniquely suited to tuberculosis pathogenesis.
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Pratik
authors.initials: P
authors.lastname: Datta
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Janani
authors.initials: J
authors.lastname: Ravi
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Guerrini
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Rinki
authors.initials: R
authors.lastname: Chauhan
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Neiditch
authors.affiliation: Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, MA, 01605, USA.
authors.forename: Scarlet S
authors.initials: SS
authors.lastname: Shell
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, 021142, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Fortune
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX, 77005, USA.
authors.forename: Baris
authors.initials: B
authors.lastname: Hancioglu
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX, 77005, USA.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Igoshin
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Gennaro
mesh_terms: D002473:Cell Wall / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000502:physiology*; D009876:Operon; D013312:Stress, Physiological