Datta, PratikRavi, JananiGuerrini, ValentinaChauhan, RinkiNeiditch, Matthew B.Shell, Scarlet S.Fortune, Sarah M.Hancioglu, BarisIgoshin, OlegGennaro, Maria Laura2017-06-062017-06-062015Datta, Pratik, Ravi, Janani, Guerrini, Valentina, et al.. "The Psp system ofﾠMycobacterium tuberculosisﾠintegrates envelope stress-sensing and envelope-preserving functions." <i>Molecular Microbiology,</i> 97, no. 3 (2015) Wiley: 408-422. https://doi.org/10.1111/mmi.13037.https://hdl.handle.net/1911/94818The 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-σE 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-σE 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.engThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Wiley.Journal articlehttps://doi.org/10.1111/mmi.13037