Secreted transcription factor controls Mycobacterium tuberculosis virulence

Raghavan, S. et al., Nature 454 (7205), 717 (2008).

Speaker: Kai-yun Lu (呂凱筠)                               Time: 13:00~14:00, Oct. 22, 2008

Commentator: Dr. Lien-I Hor (何漣漪老師)  Place: Room 601

Abstract:

     Mycobacterium tuberculosis, which causes tuberculosis, kills 2-3 million people each year and infects about one-third of the world’s population.¹ The extreme success of Mycobacterium tuberculosis as a pathogen is believed to be attributed to its capacity to modulate and evade a variety of host defence mechanisms -- a process controlled in part by a specialized type VII protein secretion system (also called the ESX-1 protein secretion system).^2,3 In a screen for ESX-1 secretion mutants, the author identified Rv3849, which encodes a secreted protein they named EspR. EspR was secreted by ESX-1 system in wild-type bacteria. However defect in EspR not only resulted in lack of EspR secretion but also diminished secretion of other factors, such as ESAT-6. Secondary structure modeling suggested that EspR had a helix-turn-helix DNA binding domain. Microarray and reporter assay showed that EspR activated transcription of an operon that includes Rv3616c-Rv3612c, whose expression are necessary for the ESX-1 system, and Electrophoretic mobility shift assay confirmed that EspR directly bound the Rv3616c promoter. Expression of tagged EspR, which blocked its secretion without compromising its transcriptional activity, resulted in enhanced repression of EspR-inhibited genes and enhanced expression of EspR-activated genes. Based on these observations, the article reveals that secretion of EspR appears to serve as a clever feedback to regulate the ESX-1 system and maintain the right level of virulence, letting Mycobacterium tuberculosis contribute to its infection for years.

References:

¹           Suganthi, P. et al., Health seeking and knowledge about tuberculosis among persons with pulmonary symptoms and tuberculosis cases in Bangalore slums. Int J Tuberc Lung Dis 12 (11), 1268 (2008).

²           Abdallah, A. M. et al., Type VII secretion--mycobacteria show the way. Nat Rev Microbiol 5 (11), 883 (2007).

³           Xu, J. et al., A unique Mycobacterium ESX-1 protein co-secretes with CFP-10/ESAT-6 and is necessary for inhibiting phagosome maturation. Mol Microbiol 66 (3), 787 (2007).