A unique Mycobacterium ESX-1 protein co-secretes with CFP-10/ESAT-6 and is necessary for inhibiting phagosome maturation

doi:10.1111/j.1365-2958.2007.05959.x

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Wiley InterScience

Molecular Microbiology

Volume 66 Issue 3, Pages 787 - 800

Published Online: 20 Sep 2007

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A unique Mycobacterium ESX-1 protein co-secretes with CFP-10/ESAT-6 and is necessary for inhibiting phagosome maturation

Junjie Xu, ^1† Olli Laine, ² Mark Masciocchi, ¹ Joanna Manoranjan, ¹ Jennifer Smith, ¹ Shao Jun Du, ³ Nathan Edwards, ⁴ Xiaoping Zhu, ⁵ Catherine Fenselau ² and Lian-Yong Gao ¹ *

¹ Department of Cell Biology and Molecular Genetics,
² Department of Chemistry and Biochemistry, and
⁴ Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20742, USA.
³ Center of Marine Biotechnology, University of Maryland Biotechnology Institute, Baltimore, MD 21202, USA.
⁵ Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary Medical, College Park, MD 20742, USA.

Correspondence to *E-mail lygao@umd.edu; Tel. (+1) 301 405 7562; Fax (+1) 301 314 9489.

^† Present address: Beijing Institute of Microbiology and Epidemiology, 20 Dongdajie, Fengtai, Beijing 100071, China.

ABSTRACT

The ESX-1 secretion system plays a critical role in the virulence of Mycobacterium tuberculosis and M. marinum. To date, three proteins are known to be secreted by ESX-1 and necessary for virulence, two of which are CFP-10 and ESAT-6. The ESX-1 secretion and the virulence mechanisms are not well understood. In this study, we have examined the M. marinum secretomes and identified four proteins specific to ESX-1. Two of those are CFP-10 and ESAT-6, and the other two are novel: MM1553 (homologous to Rv3483c) and Mh3881c (homologous to Rv3881c). We have shown that Mh3881c, CFP-10 and ESAT-6 are co-dependent for secretion. Mh3881c is being cleaved at close to the C-terminus during secretion, and the C-terminal portion is critical to the co-dependent secretion, the ESAT-6 cellular levels, and interaction with ESAT-6. The co-dependent secretion is required for M. marinum intracellular growth in macrophages, where the Mh3881c C-terminal portion plays a critical role. The role of the co-dependent secretion in intracellular growth correlates with its role in inhibiting phagosome maturation. Both the secretion and the virulence defects of the Mh3881c mutant are complemented by Mh3881c or its M. tuberculosis homologue Rv3881c, suggesting that in M. tuberculosis, Rv3881c has similar functions.

Accepted 10 September, 2007.

DIGITAL OBJECT IDENTIFIER (DOI)

10.1111/j.1365-2958.2007.05959.x About DOI