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J. Biol. Chem., Vol. 278, Issue 29, 26517-26525, July 18, 2003

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Execution of Macrophage Apoptosis by Mycobacterium avium through Apoptosis Signal-regulating Kinase 1/p38 Mitogen-activated Protein Kinase Signaling and Caspase 8 Activation^*

Asima Bhattacharyya, Shresh Pathak, Chaitali Basak, Sujata Law, Manikuntala Kundu  and Joyoti Basu 

From the Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla, Chandra Road, Kolkata 700 009, India

Macrophage apoptosis is an important component of the innate immune defense machinery (against pathogenic mycobacteria) responsible for limiting bacillary viability. However, little is known about the mechanism of how apoptosis is executed in mycobacteria-infected macrophages. Apoptosis signal-regulating kinase 1 (ASK1) was activated in Mycobacterium avium-treated macrophages and in turn activated p38 mitogen-activated protein (MAP) kinase. M. avium-induced macrophage cell death could be blocked in cells transfected with a catalytically inactive mutant of ASK1 or with dominant negative p38 MAP kinase arguing in favor of a central role of ASK1/p38 MAP kinase signaling in apoptosis of macrophages challenged with M. avium. ASK1/p38 MAP kinase signaling was linked to the activation of caspase 8. At the same time, M. avium triggered caspase 8 activation, and cell death occurred in a Fas-associated death domain (FADD)-dependent manner. The death signal induced upon caspase 8 activation linked to mitochondrial death signaling through the formation of truncated Bid (t-Bid), its translocation to the mitochondria and release of cytochrome c. Caspase 8 inhibitor (z-IETD-FMK) could block the release of cytochrome c as well as the activation of caspases 9 and 3. The final steps of apoptosis probably involved caspases 9 and 3, since inhibitors of both caspases could block cell death. Of foremost interest in the present study was the finding that ASK1/p38 signaling was essential for caspase 8 activation linked to M. avium-induced death signaling. This work provides the first elucidation of a signaling pathway in which ASK1 plays a central role in innate immunity.

Received for publication, January 27, 2003 , and in revised form, April 24, 2003.

^* This work was supported by a grant from the Department of Atomic Energy, Government of India (to J. B. and M. K.). 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.

To whom correspondence may be addressed. Fax: 91-33-23506790; E-mail: mani18{at}hotmail.com.

To whom correspondence may be addressed. E-mail: joyoti{at}vsnl.com.

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