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Molecular and Cellular Biology, March 2002, p. 1754-1766, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1754-1766.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

IAP Suppression of Apoptosis Involves Distinct Mechanisms: the TAK1/JNK1 Signaling Cascade and Caspase Inhibition

M. Germana Sanna,1 Jean da Silva Correia,1 Odile Ducrey,1,{dagger} Jongdae Lee,1 Ken Nomoto,2 Nicolas Schrantz,1 Quinn L. Deveraux,2 and Richard J. Ulevitch1*

The Scripps Research Institute, Department of Immunology, La Jolla, California 92037, and The Genomics Institute of ,1 the Novartis Research Foundation, San Diego, California 921212

Received 10 July 2001/ Returned for modification 7 August 2001/ Accepted 10 December 2001

The antiapoptotic properties of the inhibitor of apoptosis (IAP) family of proteins have been linked to caspase inhibition. We have previously described an alternative mechanism of XIAP inhibition of apoptosis that depends on the selective activation of JNK1. Here we report that two other members of the IAP family, NAIP and ML-IAP, both activate JNK1. Expression of catalytically inactive JNK1 blocks NAIP and ML-IAP protection against ICE- and TNF-{alpha}-induced apoptosis, indicating that JNK1 activation is necessary for the antiapoptotic effect of these proteins. The MAP3 kinase, TAK1, appears to be an essential component of this antiapoptotic pathway since IAP-mediated activation of JNK1, as well as protection against TNF-{alpha}- and ICE-induced apoptosis, is inhibited when catalytically inactive TAK1 is expressed. In addition, XIAP, NAIP, and JNK1 bind to TAK1. Importantly, expression of catalytically inactive TAK1 did not affect XIAP inhibition of caspase activity. These data suggest that XIAP's antiapoptotic activity is achieved by two separate mechanisms: one requiring TAK1-dependent JNK1 activation and the second involving caspase inhibition.

* Corresponding author. Mailing address: The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-8219. Fax: (858) 784-8239. E-mail: ulevitch{at}scripps.edu.

{dagger} Present address: Departement de Microbiologie, Centre Medical Universitaire, University of Geneva, Geneva, Switzerland

Molecular and Cellular Biology, March 2002, p. 1754-1766, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1754-1766.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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