Molecular Pathogenesis of M. tuberculosis infection


Transmembrane sensing of host immune effectors: The Rip1 pathway

Signal transduction across membranes through regulated intramembrane proteolysis is conserved throughout all domains of life. In the SREBP pathway of human cells, the membrane-bound SREBP transcription factors undergo sequential cleavage by site-one and site-two proteases (S1P and S2P, respectively), with human S2P being the founding member of the zinc metalloprotease family of intramembrane proteases. RseP, an E. coli S2P, cleaves the anti-Sigma factor for SigE and thereby also regulates transcription in response to environmental signals, specifically unfolded outer membrane proteins. Our original characterization of the Rip1 (Rv2869c) pathway in M. tuberculosis revealed that this S2P is a critical virulence determinant.

We have identified four anti-Sigma factor substrates of Rip1, anti-SigK, L, M, and D which regulate multiple downstream target genes. However, the virulence functions of Rip1 are independent of these sigma factor pathways. Recent work (Buglino et al, Elife 2021) has identified a new pathway downstream of Rip1 controlled by the PdtaS/PdtaR two component system that controls NO and Cu resistance through a complex set of interacting positive and negative feedback loops. Ongoing work in the lab seeks to understand the molecular details of this signal transduction system that is critical for Mtb virulence.

Present model of the Rip1 pathway

Present model of the Rip1 signal transduction system​​​​

The Proteostasis Systems of Mycobacteria

We have a long term interest in the proteostasis system of chaperones and associated factors that maintain protein solubility and function under stress. Our studies have focused on the DnaK system and its role in native protein folding, stress resistance, and antibiotic resistance.

Studies in human TB

In collaboration with our colleagues at Weill Cornell Medicine and the GHESKIO Center in Port Au Prince, Haiti, and with the support of the NIAID’s Tuberculosis Research Unit Program, we are studying the effect of antimycobacterial antibiotics on intestinal microbiome composition and the relationship of those microbiome changes to TB disease resolution.

Transmembrane sensing of host immune effectors: The Rip1 pathway

  1. Makinoshima H. and Glickman M.S., Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis. Nature, 2005. 436(7049): p. 406-9.
  2. Makinoshima H. and Glickman M.S., Site-2 proteases in prokaryotes: regulated intramembrane proteolysis expands to microbial pathogenesis. Microbes Infect, 2006. 8(7): p. 1882-8.
  3. Sklar, J.G., et al., M. tuberculosis intramembrane protease Rip1 controls transcription through three anti-sigma factor substrates. Mol Microbiol, 2010. 77(3): p. 605-17.
  4. Schneider JS, Reddy SP, E HY, Evans HW, Glickman MS. Site-2 protease substrate specificity and coupling in trans by a PDZ-substrate adapter protein. Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19543-8. doi: 10.1073/pnas.1305934110. Epub 2013 Nov 11. PubMed PMID: 24218594; PubMed Central PMCID: PMC3845159.
  5. Schneider JS, Glickman MS. Function of site-2 proteases in bacteria and bacterial pathogens. Biochim Biophys Acta. 2013 Dec;1828(12):2808-14. doi:10.1016/j.bbamem.2013.04.019. Review. PubMed PMID: 24099002; PubMed CentralPMCID: PMC4097180.
  6. Schneider JS, Sklar JG, Glickman MS. The Rip1 protease of Mycobacterium tuberculosis controls the SigD regulon. J Bacteriol. 2014 Jul;196(14):2638-45. doi: 10.1128/JB.01537-14. Epub 2014 May 9. PubMed PMID: 24816608; PubMed Central PMCID: PMC4097585.
  7. Buglino JA, Sankhe GD, Lazar N, Bean JM, Glickman MS. Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection. Elife. 2021 May 18;10:e65351. doi: 10.7554/eLife.65351. PMID: 34003742; PMCID: PMC8131098.

The Proteostasis Systems of Mycobacteria

Studies of the role of the microbiome in TB disease resolution with antibiotic therapy