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J. Biol. Chem., Vol. 282, Issue 2, 1039-1050, January 12, 2007

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Execution of Macrophage Apoptosis by PE_PGRS33 of Mycobacterium tuberculosis Is Mediated by Toll-like Receptor 2-dependent Release of Tumor Necrosis Factor-^*

Sanchita Basu¹, Sushil Kumar Pathak¹², Anirban Banerjee, Shresh Pathak, Asima Bhattacharyya³, Zhenhua Yang, Sarah Talarico, Manikuntala Kundu, and Joyoti Basu⁴

From the Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India and the Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan 48105

Combating tuberculosis requires a detailed understanding of how mycobacterial effectors modulate the host immune response. The role of the multigene PE family of proteins unique to mycobacteria in the pathogenesis of tuberculosis is still poorly understood, although certain PE_PGRS genes have been linked to virulence. Tumor necrosis factor- (TNF-) is essential for successfully combating tuberculosis. In this study we provide evidence that PE_PGRS33, a surface exposed protein, elicits TNF- release from macrophages in a TLR2 (Toll-like receptor 2)-dependent manner. ASK1 (apoptosis signal-regulating kinase 1) is activated downstream of TLR2. ASK1 activates the MAPKs p38 and JNK. PE_PGRS33-induced signaling leads to enhanced expression of TNF- and TNF receptor I (TNFRI) genes. Mycobacterium smegmatis expressing PE_ PGRS33 elicits the same effects as purified PE_PGRS33. TNF- release occurs even when internalization of the bacteria is blocked by cytochalasin D, suggesting that interaction of PE_ PGRS33 with TLR2 is sufficient to trigger the effects described. Release of TNF- plays the determining role in triggering apoptosis in macrophages challenged with PE_PGRS33. The death receptor-dependent signals are amplified through classical caspase 8-dependent mitochondrial release of cytochrome c, leading to the activation of caspases 9 and 3. An important aspect of our findings is that deletions within the PGRS domain (simulating those occurring in clinical strains) attenuate the TNF--inducing ability of PE_PGRS33. These results provide the first evidence that variations in the polymorphic repeats of the PGRS domain modulate the innate immune response.

Received for publication, May 8, 2006 , and in revised form, October 30, 2006.

^* This work was supported in part by a grant from the Department of Science and Technology, Government of India (to J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported by a fellowship from Council of Scientific and Industrial Research, Government of India.

³ Present address: Dept. of Medicine, Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA 22903.

⁴ To whom correspondence should be addressed. Fax: 913323506790; E-mail: joyoti{at}vsnl.com.

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